key: cord-287758-da11ypiy
authors: Mônica Vitalino de Almeida, Sinara; Cleberson Santos Soares, José; Lima dos Santos, Keriolaine; Emanuel Ferreira Alves, Josival; Galdino Ribeiro, Amélia; Trindade Tenório Jacob, Íris; Juliane da Silva Ferreira, Cindy; Celerino dos Santos, Jéssica; Ferreira de Oliveira, Jamerson; Bezerra de Carvalho Junior, Luiz; do Carmo Alves de Lima, Maria
title: COVID-19 therapy: what weapons do we bring into battle?
date: 2020-09-10
journal: Bioorg Med Chem
DOI: 10.1016/j.bmc.2020.115757
sha: 
doc_id: 287758
cord_uid: da11ypiy

Urgent treatments, in any modality, to fight SARS-CoV-2 infections are desired by society in general, by health professionals, by Estate-leaders and, mainly, by the scientific community, because one thing is certain amidst the numerous uncertainties regarding COVID-19: knowledge is the means to discover or to produce an effective treatment against this global disease. Scientists from several areas in the world are still committed to this mission, as shown by the accelerated scientific production in the first half of 2020 with over 25,000 published articles related to the new coronavirus. Three great lines of publications related to COVID-19 were identified for building this article: The first refers to knowledge production concerning the virus and pathophysiology of COVID-19; the second regards efforts to produce vaccines against SARS-CoV-2 at a speed without precedent in the history of science; the third comprehends the attempts to find a marketed drug that can be used to treat COVID-19 by drug repurposing. In this review, the drugs that have been repurposed so far are grouped according to their chemical class. Their structures will be presented to provide better understanding of their structural similarities and possible correlations with mechanisms of actions. This can help identifying anti-SARS-CoV-2 promising therapeutic agents.

The world is facing a huge challenge in the coronavirus disease (COVID-19) pandemic: How to fight an enemy without weapons in terms of therapy? Unfortunately, even before the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) worldwide spread, there were no clinical treatments nor prevention strategies available for any human coronavirus. 1 It is understandable that both society and researchers urge the discovery of new compounds or even of a drug that is commercially available that can be employed by physicians mainly for patients with the extreme presentation of COVID-19. There is also urgency in the discovery of medicine with prophylactic action to prevent the entry of the virus in host cells after exposure. Vaccine research experts already indicate that rescue from SARS-CoV-2 will come from a long but effective journey to produce a vaccine. 2 While this is not a reality, the scientific community, including medicinal chemists and doctors who accompany patients, are trying to identify therapeutic alternatives. This is a meritorious attitude: The commitment with the protection of humanity. Nevertheless, the rigorous feature of science in the discovery of a new drug cannot be disregarded, even during a pandemic and in the face of the urgent demand for a treatment, to avoid eventual mistakes and spurious hope.

The increase in studies related to SARS-CoV-2 during the first semester in 2020 has allowed the rather speedy identification of promising therapeutic targets for both developing immunotherapies and producing/identifying antiviral drugs. It is noteworthy the increase in outbreaks of SARS-CoV (2002) and MERS-CoV (2013), with accelerated production of knowledge on these HCoVs, which has been very useful for ongoing investigations on SARS-CoV-2. One example is the availability of technological devices that allowed the fast sequencing of SARS-CoV-2 genome and the elucidation of a promising antigen target, the S glycoprotein. Nonetheless, the development of a human vaccine can take years, especially because employing emergent technologies requires extensive safety tests and expansion to large scale production in order to assist the world population, as demanded in the case of the COVID-19 pandemic. 3 The development of new medicine also demands many years of research that involve stages of reasonable planning, synthesis, structural characterization, formulation of prototypes, preclinical and clinical trials. Therefore, the literature highlights, as alternative treatments for COVID-19, the repurposing of drugs, which is fast and useful in emergencies such as the one experienced today. The repurposing of drugs means the use of broad-spectrum medicine for a new disease, once its metabolic characteristics, doses, potential efficacy and adverse effects are pre-established due to drug studies extracellular liquid volume and arterial pressure of the human body. It is largely expressed in fifteen human tissues, including ciliated bronchial epithelial cells and type II pneumocytes form pulmonary alveoli, the main location of lesions caused by SARS-CoV-2. 36, 37 After ACE2 receptor-binding, a conformational alteration occurs in protein S allowing the fusion between the viral envelope and the host cell membrane via endosomal. Then, SARS-CoV-2 releases the RNA into the cytoplasm to be translated into viral replicase polyproteins pp1a and pp1ab, which are processed by 3CL pro and PL pro proteases, respectively. The cleavage products are 16 Nsps that form the transcription and replication complex. 38 Next, the positive RNA strand is translated into a template of negative strand that allows the synthesis of new genomics and sub genomics mRNAs.

These mRNAs are translated and transcribed producing structural and accessory proteins. Viral proteins and RNA genomic are put together in virions at endoplasmic reticulum and Golgi complex, finally transported through vesicles and released from the cell host for infecting new cells. 38, 39 The COVID-19 symptomatology starts after the virus is installed in host cells. In general, the symptoms include lasting and high fever, dry cough, shortness of breath, muscles aches or tiredness, sputum production, headaches, and a small percentage of individuals presented gastrointestinal symptoms such as diarrhoea and vomit. 40 The incubation period of SARS-CoV-2, from exposure to first symptoms, lasts 2 to 14 days. The pre-symptomatic stage lasts from 1-3 days (possibly more) before the beginning of symptoms. The post-symptomatic stage lasts at least 7 days after the beginning of symptoms and 3 days after lowering of fever and improvement of respiratory symptoms. 41 There are many unanswered questions such as the duration of potential immunity of both symptomatic and asymptomatic individuals when infected with SARS-CoV-2. 31 It is noteworthy that efficient strategies to fight the disease should not depend on the symptoms of patients, once asymptomatic or pre-symptomatic subjects can play an important role in the direct and indirect transmission to others, as demonstrated by Arons et al. 42 This investigation reports that half the residents in a nursing facility, who tested positive, were asymptomatic when tested and probably contributed to the transmission to other residents. Thus, control strategies focused on symptomatic residents were not sufficient to prevent transmission once SARS-CoV-2 had been introduced in the facility.

Laboratory exams of infected patients showed alterations in haematology and biochemistry.

It was verified the increase of leukocytes and the reduction of lymphocytes; increased D-dimer and erythrocyte sedimentation rate (ESR), prolongation in prothrombin times (PT), followed by increase in bilirubin levels, aspartate transaminase (AST), alanine transaminase (ALT), creatinine, lactate dehydrogenase (LDH), protein C reactive (PCR), hypoalbuminemia (low albumin), microcytosis and thrombocytopenia. 43 In addition, inflammatory factors that indicate the immune condition of patients, such as interleukins (IL) IL-2, IL-6, IL-7, and IL-10 and the tumoral necrosis factor-α (TNF-α) become elevated. Plasma levels of Granulocyte-colony stimulating factor (GCSF), protein induced by interferon gamma, Monocyte Chemoattractant Protein-1 (MCP-1), macrophages inflammatory protein 1α and TNF-α also display significant increase. 44 Potential risk factors or comorbidities that can lead to complications of COVID-19 include elderly individuals (specially above 65 years of age), cardiovascular issues, cerebrovascular, chronic pulmonary diseases, immunocompromising, renal problems, hepatic disease, hypertension, diabetes and obesity. [44] [45] [46] [47] [48] [49] There is a notorious concern regard the medicine administered to fight these comorbidities because some of them can lead to greater expression of ACE2, such as treatments for diabetes 48 or hypertension. 50 This may favour or even aggravate COVID-19 infection. These facts justify the urgency of research that contemplate alternative therapeutic targets such as calcium channels blockers for hypertensive individuals as suggested by Fang et al. 48 However, there is little clinical evidence on the risk of treating COVID-19 patients with therapies that induce greater expression of ACE2. Further investigation is necessary to explore whether these medicines inhibit or trigger the viral entry into the cells of an infected host. 51 A frequent report in epidemiological data regarding the mortality of COVID-19 concerns the sex of individuals, as men are the predominant fatal victims of the disease. Therefore, being of the male sex is considered a bad prognostic factor for infection. 52 ,53 A possible explanation lies in the relation between gonadal hormones and the expression of ACE2 enzymes or even an alleged Vitamin D deficiency, according to Vignera et al. 54 The latter suggest monitoring of serum levels of testosterone and Vitamin D in infected patients for a better understanding of the different fatality rates between sexes, including the hypothesis that women's hygiene justify a lesser rate of infection.

Understanding the pathogenic effects of SARS-COV-2 for the different organs affected by the disease has also been object of investigation, such as gut-lung crosstalk. 55 Data from research conducted thus far indicate that the infection caused by SARS-COV-2 is not only capable of causing pneumonia, but it can also damage other organs such as the heart, the liver, the kidneys and organic systems such as the blood and the immune system. 44, 56, 57 Patients with the extreme form of the disease frequently manifest lymphopenia, 30, 57 hepatic insufficiency 58 and viral sepsis diagnostic, 51 whose complications can be related to the severity of the cases and the mortality of patients. 56, 57 There are reports that the eventual death of such patients is due to multiple organ insufficiency, acute respiratory distress syndrome (ARDS), cardiac insufficiency, arrhythmia and renal insufficiency. 56, 59 Therefore, great attention is necessary to the disease's potential damage to multiple organs and to therapeutic alternatives to fight COVID-19, 60 given that some of these alternatives can have side effects on organs initially unrelated to the respiratory system, but that may be susceptible to a systemic compromise prompted by the virus once the treatment has begun.

Hence, it is possible to observe the existence of different forms of aggravating the disease. 41 In this regard, Wang et al. 60 recommend the creation of a system to categorize patients with the severe form of COVID-19. Several investigations report that all HCoVs, SARS-CoV, MERS-CoV and SARS-CoV-2 induce exaggerated immune responses in the host, which are associated to the severity of pulmonary pathology and might lead to the development of acute respiratory distress syndrome (ARDS) or death. 57 The incidence of the extreme form of the infection is associated with cytokine storm syndrome, characterized by high plasma concentration of several interleukin, inflammatory cytokine, inflammatory chemokines, among other factors that cause infiltrated inflammatory in the organs. 44, 61, 62 Survivors of this excessive response by the immune system can develop long-term fibrosis and pulmonary damages that might culminate in functional injuries to these organs, thus reducing the patient's quality of life. 63 

During the development of drugs to fight microorganisms, the adoption of strategies that allow the design of molecules to act against specific biological targets of bacteria, parasites or viruses is preferred. Therapies for CoVs can be divided into several categories, based on specific paths: (1) CoVs proteins or functional enzymes that are essential for viral replication; (2) structural proteins of the virus that prevent its binding to the respective receptors in human cells or its assembly process;

(3) some viral factor that restores the host's inherent immunity and; (4) host-specific enzymes or receptors, that prevent the entry of the virus in the host cells. 5, 64 So far, structural proteins and enzymes that participate actively in the process of viral replication are the most investigated targets for the development of molecules for anti-CoVs therapies (FIG. 1) . Investigations by Wu et al. 5 through bioinformatics, analysed possible SARS-CoV-2 therapeutic targets. The proteins coded by this virus were verified and compared to proteins coded by other CoVs. The results enabled the detection of structural similarities to SARS-CoV, from which it was possible to conduct homology modelling to build 19 proteins for SARS-CoV-2. Among the targets were spike (S) glycoprotein, Nsp (RNA-dependent RNA polymerase -RdRp), enzyme helicase (3CL pro and PL pro ), TMPRSS, ORF7a factor and ACE2 presents in the host cells. 5 These targets have pivotal roles in the development of the virus and have great influence on its pathogenicity, hence, some details are provided next.

Molecular modelling showed that spike (S) glycoprotein is a transmembrane protein of approximately 180 to 200 kDa type I whose N-terminal turns to the exterior of the virus and its Cterminal segment turns to the interior of the virus. The typical structure of CoVs is given by the assemble of a bulbous projection of a corolla as trimers of protein S and it is cleaved into two important subunits from the pathogenic perspective: S1 and S2. SARS-CoV and SARS-CoV-2 (S) glycoprotein share about 76% of amino acid identity and enable the entry of the virus in the host cells.

Therefore, S glycoprotein present in CoVs has been considered a promising biological target for antiviral mechanisms. 35, 65 The moment when the virus approximates the target cell prompts the recognition by the receptor-binding domain (RBD) in the S glycoprotein of its receptor, which leads to the binding to subunit S1. Next, the subunit S2 allows fusion of viral and cellular membranes, which enables entry in the cell and the release of viral RNA genome. 35, 66, 67 Some investigations suggest that the strong binding affinity between S protein and ACE2 is essential for viral entry, hence, ACE2 is also relevant for the development of drugs. 5, 68 Molecules that bind to the surface of the virus can destabilize the formation of S glycoproteins and interfere both with the trimerization of the protein and with the continuity of the life cycle of CoVs. 69 Several studies have been conducted on S protein to clarify its SARS-CoV-2 structure and its binding process as well as to evaluate its relevance as target for in-silico and in-vitro assays on molecules for anti-SARS-CoV-2 therapies. One study conducted by Hoffman et al. 35 investigated how the SARS-CoV-2 S protein facilitates viral entry in the target cells and how this process could be blocked. Results showed that ACE2 is used as receptor for the entry of SARS-CoV-2 in host cells and that the spread of this CoV in the infected host depends on the activity of TMPRSS2 (a cellular serine protease responsible for initiating the binding process between S protein and ACE2). This process can be blocked with clinically approved TMPRSS2 inhibitor. Prior to this, the relevance of TMPRSS2 was highlighted in the dissemination of several types of viruses such as Influenza A and other CoVs, which also makes it a relevant target for COVID-19 therapeutic intervention. [70] [71] [72] [73] [74] [75] [76] Binding between S proteins and ACE2 receptors was corroborated through X-ray crystallography conducted by Lan et al. 67 to elucidate the interaction between the SARS-CoV-2 RBD and ACE2 at a higher resolution. In spite of different interactions with ACE2, the SARS-CoV-2 RBD /ACE2 and SARS-CoV RBD /ACE2 interfaces share a substantial similarity regarding the surface area, the number of interacting residues and the networks of hydrophilic interactions. Such similarity strongly points to a convergent evolution of both SARS-CoV-2 and SARS-CoV RBD structure which improves the binding affinity for the same receptor, the ACE2. The non-conserved RBD regions in S protein, such as subunit S2, could be potential targets for cross-reactive antibodies. Considering RBD as a critical region for receptor binding, antibodies that target the conserved epitopes in the RBD are also good candidates for the development of highly potent cross-reactive therapeutic agents against several species of CoVs, including SARS-CoV-2. 67 Investigations on ligands obtained from DrugBank 5.1 used molecular Docking to identify target regions in the pockets of the quaternary structure of SARS-CoV-2 S glycoprotein (from Protein Data Bank-PDB). Six pockets present in S glycoprotein deserve further investigation in medicinal chemistry due to suitable features for small molecule binding. Among the six pockets, the eight best ligand candidates from DrugBank were all binding pocket #1, which contained residues of amino acids Proline, Leucine, Lysine, Asparagine, Phenylalanine, Glycine, Threonine, Glutamine, Alanine, Methionine and Tyrosine. One of the best ligands was the drug Saquinavir, an antiviral from the class of protease inhibitors, used in anti-HIV therapy. 69 Nsps are involved in the RNA transcription, translation, protein synthesis, processing and modification, viral replication and infection of the host. Significant functional proteins, 3CL pro , PL pro , helicases and RdRp are important targets for the development of small-molecule inhibitors, due to their biological function and vital enzyme active site. 77 Factors Nsp1, Nsp3c and ORF7a are related to assistance to the immune evasion of SARS-CoV-2. Interaction between Nsp 1 and the host ribosomal subunit induce the degradation of mRNA, allowing the virus to develop resistance to the host innate immunity. Binding between ORF7a and Bone marrow matrix antigen 2 (BST-2) inhibits activity and blocks BST-2 glycosylation. These results suggest that all three structures are potential targets for antiviral medicine. 5 Proteases PL pro and 3CL pro mediate the proteolytic cleavage of polypeptides produced by βcoronavirus SARS after genome transcription, thus generating other proteins. The 3CL pro , known as Nsp5, cleavages several non-structural proteins of importance for viral replication and the maturation of Nsps, which is essential in the life cycle of the virus. Therefore, it is an attractive biological target for that has been inhibited in-silico by several antiviral, anti-inflammatory and anti-hypertensive drugs from the database ZINC (FDA). 5 In addition, docking and molecular dynamic studies conducted by Qamar et al. 78 showed that non-toxic natural products formed strong bonds with SARS-CoV-2 catalytic dyad Cis145-His41 of 3CL pro .

Moreover, the proteinase PL pro is responsible for cleavages of N-terminus in the replicase polyprotein to release Nsp1, Nsp2 and Nsp3, which are essential for correcting virus replication significant to antagonize the host's innate immunity. Analysis of the docking model showed that ribavirin formed Hydrogen bonds with residues Gly164, Gln270, Tyr274, Asp303 as well as hydrophobic interactions between Tyr265 and the PL pro residue. These results indicate ribavirin as a powerful PL pro enzyme inhibitor, which means it has promising features for anti-COVID-19 therapy given the inhibition of a likely PL pro therapeutic target. 5 Helicase (Nsp13) has been identified as a promising target for antiviral drug discovery, particularly against SARS-CoV-2. It is a multifunctional protein necessary for a wide range of biological processes, such as genome replication, recombination and dislocation of proteins related to chromatin and nucleic acid remodelling. For CoVs, helicase is indispensable for viral replication.

In studies on molecular modelling, several antibacterial, antifungal and antiviral drugs were analysed and presented elevated affinity to helicase, suggesting it as a good target for SARS-CoV-2 therapy. 5 RNA-dependent RNA polymerase (RdRp -also nominated Nsp12) catalyses the viral RNA, which performs a key role in the replication/transcription complex of SARS-CoV-2, possibly aided by Nsp7 and Nsp8 complex as cofactor. 5, 79 Nsp12 has been studied as potential target for several SARS-CoV and MERS-CoV inhibitors, due to its importance for viral control. Satisfactory results of RdRp inhibition by several ligands were presented in the modelling studies by Gao et al. 79 

Yin et al. 80 Those ligands included antiviral analogous to nucleotides, such as Remdesivir, which already shows great potential in the treatment of COVID-19 infections. In addition, some nonstructural proteins, including Nsp3b, Nsp3e, Nsp7, Nsp8, Nsp9, Nsp10, Nsp14, Nsp15 and Nsp16, also stood out as useful targets due to their significant role in the synthesis and replication of viral RNA. 5 3CL pro is key enzyme for CoVs, also called Main protease (M pro ), that plays a pivotal role in mediating viral replication and transcription, making it an attractive target for anti-SARS-CoV-2 drugs. Such claim is reinforced by studies by Jin et al. 81 after the virtual screening of N3 inhibitor.

Results show that N3 (1) is a time-dependent irreversible inhibitor of this enzyme and that a stable covalent bond is formed between N3 and 3CL pro . High-throughput screening (HTS) was applied to 10,000 drugs and drug candidates, demonstrating that Ebselen (2), PX-12 (3) and Carmofur (4) are all able to covalently bind to 3CL pro do SARS-CoV-2, with IC 50 that varied from 0.67 to 21.4 µM (FIG. 2) . It is likely that a part of the hits identified by HTS are bonded to the catalytic cysteine of 3CL pro through their sulfhydryl groups. In-vitro studies on antiviral activity were performed to corroborate the results. Real Time Quantitative PCR (qRT-PCR) demonstrated that Ebselen and N3 had the strongest antiviral effects at a concentration of 10 μM treatment in SARS-CoV-2 infected Vero cells. After plaque-reduction assay, the dose-response curves suggested that both could penetrate cellular membrane to access their targets. This result strongly supports the hypothesis that developing a single antiviral agent targeting 3CL pro or in combination with other therapies could provide an effective first line of defence against all CoVs related diseases.

In relation to SARS-CoV-2 therapy, some of the aforementioned targets have been explored for both new drug proposition as well as for SARS-CoV-2 drug repurposing. Our focus is on this last type, and for each medicine, the putative mechanism of action and viral target will be described trying to find an understandable rational therapy even for an immediate illness situation like COVID-19 pandemic. Carmofur (4).

As previously mentioned, SARS-CoV-2 is an enveloped virus, whose nucleocapsid consists of a positive RNA genome surrounded by multiple copies of nucleocapsid protein. This virus, after entry in the host cell, replicates fast the viral genome with new virion production. The RNA replication into the cell host depends on enzymes and substrates for RNA synthesis, such as ribonucleotides (adenine, guanine, cytosine or uracil) that have nitrogenous bases in the purine or pyrimidine classes. Compounds can mimic these chemical structures and interfere with the formation or use of one of these essential normal organism metabolites. The interference is generally prompted by enzyme inhibition in the biosynthetic pathway of the metabolite or by incorporation, as a false building block, into vital macromolecules such as proteins and polynucleotides. So, this class of therapeutic agents is called antimetabolites. 82, 83 Diverse antimetabolites have been indicated as promising anti-SARS-CoV-2. They are described next.

Pyrimidine derivatives are aromatic organic compounds necessary for all life forms. Examples of pyrimidine derivatives are nitrogenous bases cytosine (5), uracil (6) and thymine (7) (FIG. 3) . They are found in DNA and RNA and participate in the metabolic process that involves carbohydrate and lipids. 84, 85 These heterocyclic rings share two nitrogen atoms at 1 and 3 positions, but display variations between themselves, such as an amine group at 4-position in the cytosine and a methyl at 5-position in the thymine. From the pharmacologic perspective, nitrogenous bases are investigated as pharmacophores and are found in the structure of many drugs and experimental substances with various activities, 86 such as antitumoral, 87 antibacterial, 88 antiparasitic, 89 and antiviral. 90, 91 Regarding antiviral activity, there are several approved drugs that are classified as pyrimidine nucleotide biosynthesis inhibitors (PNBI) because, after phosphorylation, they are incorporated either into the DNA or into the RNA and inhibit hosts or pathogenic enzymes, such as polymerases. 85 Therefore, the likely mechanism of action of some pyrimidine derivative drugs has been considered for repurposing. Some pyrimidine derivatives with antiviral activity are often formulated as prodrugs.

This format solves issues of high polarity in its final structure prompted by the phosphonic acid, which interferes with pharmacological properties and causes low cellular permeability and low oral bioavailability. 91

One compound appointed as potential anti-SARS-CoV-2 is the 5-Fluorouracil (8) (5-FU) (FIG. 3) , a heterocyclic aromatic amine similar to uracil (U) that presents a fluorine-carbon bond at 5-position. This compound is used in the treatment of oesophageal cancer, 83 stomach cancer, 92 breast and colon cancer. 93 The similarity between 5-FU and uracil allows the direct action on nuclei acid as it is incorporated into the genetic material and inhibits replication. 83 Tests with 5-FU as monotherapy confirmed its failure against any coronaviruses. The reason proposed to such failure relied on the fact that coronaviruses RNA proofreading activities involve a 3' → 5' exoribonuclease in the Nsp14, which removes 5-FU during replication and metabolism. Hence, the combination between 5-FU and deoxyribonucleoside and deoxyribose was suggested so that, after its insertion in the RNA, it escapes RNA proofreading and prompt lethality and/or lethal mutagenesis in the virus. Despite the proposition of using a widely marketed drug to treat several types of cancer, which means it has well-established efficiency and safety, no other type of test has been made to confirm its efficacy against SARS-CoV-2. Therefore, further experiments are necessary to explore 5-FU potentialities. 94

Another antitumoral drug considered for its anti-SARS-CoV-2 potential is gemcitabine (GCT) (9) (FIG. 3) , an analogue of deoxycytidine whose pharmacological action is triggered after the intracellular transformation into triphosphate gemcitabine. The latter competes with endogenous nucleoside triphosphates by incorporation into the genetic material, thus inhibiting DNA synthesis. 95

Initially, GCT was developed for antiviral activity, however, initial results caused it to be redirected for anticancer therapy. It became, then, widely used against non-small cell lung cancer, pancreas, bladder and breast cancers as well. [96] [97] [98] In-vitro analyses of gemcitabine hydrochloride inhibited MERS-CoV and SARS-CoV, with a CE 50 of 1.2 μM and 4.9 μM, respectively, in addition to low cell toxicity for VERO E6 cells. 99, 100 These data are indicative of a possible activity against SARS-CoV-2, but complementary preclinical investigations are necessary before clinical trials. Albeit considered a safe drug under predetermined doses, GCT adverse effects are noteworthy and include myelosuppression and disruption of liver functions.

In February 2017, the European Union (EU) approved Baricitinib (10) as second-line oral treatment for mild to severe active rheumatoid arthritis in adults. 9 A differential feature of Baricitinib structure is the azetidine ring bearing an ethylsulfonyl, beyond an acetonitrile group at 3-position.

The same ring binds to the N atom at 1-position in the pyrazole, which, in its turn, binds to the pyrimidine conjugated to a pyrrole ring. 101 This medicine can modulate human innate and adaptive immune system. Based on this property, presumably, one of the important mechanisms of action of baricitinib in the treatment of rheumatoid arthritis is the inhibition of the IL-6 / JAK1 / JAK2 pathway. 102 The promising nature of Baricitinib and other small molecule inhibitors against SARS-CoV-2 was pointed by Richardson et al. 9 through in-silico tests using Benevolent AI. The authors evaluated 378 compounds to show that sunitinib (11) and erlotinib (12) inhibit AP2-associated protein kinase 1 (AAK1) interrupting the virus entry to the cells and the intracellular assembly of new viral particles (FIG. 3) . Regarding these two antitumor drugs, it is known that sunitinib is an oral oxindole multitargeted kinase inhibitor that inhibits certain tyrosine kinases including vascular endothelial growth factor receptors (VEGFR types 1 and 2), platelet-derived growth factor receptors (PDGFR-α and PDGFR-β), stem cell factor receptor (KIT), FMS-like tyrosine kinase-3 (FLT3), glial cell-line derived neurotrophic factor receptor (RET) and the receptor of macrophage-colony stimulating factor (CSF1R). 103 Concerning erlotinib, it was developed as reversible and highly specific small-molecule tyrosine kinase inhibitor that competitively blocks the binding of adenosine triphosphate to its binding site in the tyrosine kinase domain of epidermal growth factor receptor (EGFR), thereby inhibiting autophosphorylation and blocking downstream signalling. 104 However, these oncological drugs have serious adverse effects such as diarrhoea, loss of appetite and skin rashes. In addition, high doses of these medications can aggravate those effects.

In relation to baricitinib, its anti-SARS-CoV-2 potential was explained in three ways: AAK1

inhibition like sunitinib and erlotinib; the kinase associated to cyclin G, which is another endocytosis regulator; and the Janus kinase, that inhibits the action of cytosines that triggers the inflammatory process. Because Baricitinib can inhibit AAK1 at the therapeutic dose (2 or 4 mg/day), the drug is indicated for clinical trials. It is highlighted that Baricitinib is not indicated for patients with neutropenia or lymphopenia, once it lowers rates of neutrocytes and lymphocytes, which can lead the disease to progress and increase anaemia. Furthermore, treatment with Baricitinib can reactivate varicella-zoster, herpes simplex and Epstein-Barr viruses. This implicates in a conflict between the potential effect and the adverse effects of Baricitinib against COVID-19 to prevent aggravating the disease and the mortality of patients. 105

An analogue of adenosine, Galidesivir (GSV) (13) is a broad-spectrum antiviral drug that blocks viral RNA polymerase by replacing a natural nucleotide with galidesivir triphosphate. This alteration prompts changes in electrostatic interactions and prevents the formation of the RNA elongated strand. 106, 107 Adenosine and GSV differ in that galidesivir has one Carbon at 7-position in the pyrimidine ring and Nitrogen in the ribose ring, whereas adenosine has one Nitrogen in the former and Oxygen in the latter (FIG. 2) . 106 It is noteworthy that GSV has not been approved for clinical trial and is an experimental drug in advanced stages of development. 108 GSV was first developed against hepatitis C (HCV) but first clinical trials were conducted to ensure its safety (in healthy individuals) and efficacy against yellow fever. Furthermore, GSV displayed in-vitro and in-vivo antiviral activity against Filoviridae, Alphavirus, bunyavirus, arenavirus, paramyxovirus, flavivirus, orthomyxovirus, picornavirus and SARS and MERS coronaviruses. 11, 106, 109 Recent in-silico studies have shown the existence of a strong bond between GSV and SARS-CoV-RdRp to demonstrate the capacity of alterations in RNA polymerase, which can eradicate the virus. Although, preclinical and clinical trials are necessary to either confirm or deny this hypothesis. 7 It is noteworthy that investigations have pointed the inactivity of GSV against SARS-CoV-2 at concentrations lower than 100 mΜ. 110 The existence of antiviral activity against other coronaviruses indicates that more investigations on GSV against SARS-CoV-2 are required to elucidate its potential activity in advanced testing.

Next, sofosbuvir (SBV) (14) is an example of successful nucleotide prodrug, approved by the Food Drug Administration (FDA) since 2013, against chronic hepatitis C infections. SBV is also combined with other antiviral drugs, such as ledipasvir, velpatasvir and voxilaprevir. 111, 112 The structural similarity between SBV (FIG. 2) and uridine allows that drug to act on HCV RdRp, incorporate itself into the viral RNA and terminate the synthesis of the nucleotide sequence. 82 Structural analysis of SBV revealed that its elevated potential is partly due to the presence of the 5'phosphate, which terminates the primary enzyme transformation monophosphate inhibitor. 113 The antiviral activity has been explored against other viruses through in-vitro and in-silico studies and shown potential for inhibiting the dengue virus, 114 yellow fever, 115 

Telbivudine (TBV) (15) (FIG. 3) is a thymidine nucleoside analogue used with specific activity against the hepatitis B virus (HBV). It starts acting after phosphorylation by cellular kinases, which results in the active metabolite, Telbivudine 5'-triphosphate, enabling DNA polymerase and inhibiting viral replication. The hydroxyl at 3-position in the sugar β-L-2'-desoxirribose provides specificity to HBV polymerase. 120 Suggesting repurposing TBV to fight COVID-19 was prompted by virtual screening to find drugs that act on viral M pro . Among other results were Ribavirin, TBV and two vitamins, cyanocobalamin (B12) and nicotinamide (B3). Researchers suggest that these four drugs can be combined and used against COVID-19, once they are safe, marketed and approved by the authorities. 8 Notwithstanding, the suggestion of repurposing these drugs requires more information, including on drug interaction parameters. In spite of well-tolerated and safe for monotherapy, associating TBV and ribavirin, another antiviral drug, can increase hepatotoxic activities of TBV. 121, 122 It is also important to consider the elevated risk of resistance to TBV, which and pyrimidine derivatives drugs: 5-Fluorouracil (8); Gemcitabine (9); Baricitinib (10); Sunitinib (11); Erlotinib (12); Galidesivir (13); Sofosbuvir (14) ; Telbivudine (15).

Purine is a 5 and 6-membered bicyclic ring. Similar to pyrimidines, purine derivatives are essential to life. They are basic constituents of nitrogenous bases adenine (A) (16) and guanine (G) (17) (FIG. 4) . 84 The safety of RDV for humans infected with EBOV was evaluated in the Democratic Republic of Congo. Results confirmed its safety but did not point RDV as the best therapeutic option, once its mortality rate reached 53% of treated group. 133 It has been proved that GS-5734 inhibits epidemic and zoonotic HCoV. 134 of viral loads and weight loss in murine. 135 Therefore, RDV is a potential drug to treat MERS-CoV infections.

Regarding COVID-19, RDV was used to treat the first US case. The patient was 35 years old, had slight cough, low fever and no evidence of pneumonia at day 4 of the disease. When the clinical symptoms became worse, the patient was given vancomycin and cefepime. As the symptoms worsened, intravenous treatment with RDV was administered at day 7, and vancomycin and cefepime were no longer administered. At day 8, the patient displayed clinical improvement, unfortunately details on the doses and duration of treatment were not provided. 136 After this first case, a clinical trial with a larger number of COVID-19 patients was conducted. 137 This study of efficacy involved 53 patients infected with SARS-CoV-2 who displayed saturation equal or inferior to 94% while they were breathing ambient air or receiving oxygen support. The treatment lasted 10 days, patients were given 200 mg intravenously on day 1, followed by 100 mg daily for the remaining 9 days of treatment.

Follow up of patients treated for 18 days indicated that, after the first dose of RDV, 68% improved oxygen support whereas 15% of patients got sicker, 47% were discharged and mortality rate was 13%. The most common adverse events (60% of patients) were increased hepatic enzymes, diarrhoea, rash, renal impairment, and hypotension. Some limitations were noted in the study, such as the small size of the cohort, the short duration of follow-up and the lack of information on the patients. Hence, the efficacy of RDV requires validation by the ongoing randomized, placebo-controlled trials.

One advantage of repurposing RDV is the availability of data on safety and pharmacokinetics, which were obtained previously at phase 1 clinical trial. 

In addition to the promising results shown by RDV, other purine analogues have been investigated for SARS-CoV2. Ganciclovir (GCV) (19) also named, according to its chemical structure, 9-(1,3-dihydroxy-2-propoxymethyl) guanine (FIG. 4) , is a guanine analogue, similar to acyclovir, except for the bond between the methyl group and one hydroxyl. GCV inhibits the Human Herpesvirus and is also indicated in the treatment of cytomegalovirus infections related to Acquired Immunodeficiency Syndrome (AIDS). 139 GCV is converted into ganciclovir triphosphate by cellular kinase, which inhibits dGTP and disrupts viral DNA synthesis due to substitution of various adenosine bases in the DNA chain. 140 Recently, GCV was used to treat COVID-19 patients in China. 141 The drug was administered with other antivirals, such as oseltamivir and Kaletra. As a descriptive study, the relation between GCV as key factor in clinical outcome of the 99 patients (31% of which were discharges) was not possible. 141 Therefore, GCV efficacy as monotherapy or part of combined therapy is yet necessary for more robust investigations.

Valganciclovir (20) (FIG. 4) is the antiviral prodrug of GCV taken by mouth. It is indicated for the same treatments as GCV (cytomegalovirus in people who have acquired immunodeficiency syndrome, gastrointestinal disorders related to AIDS). The drug has great bioavailability and is converted by hydrolysis into ganciclovir. Using valganciclovir in its oral form enables clinical treatment and makes patients more comfortable. [142] [143] [144] The mechanism of action is the same of GCV. 145 Valganciclovir was computationally evaluated for COVID-19. 5 The assay with the main proteins coded for SARS-CoV-2 allowed the determination of 21 possible binding targets, of which 19 were proteins and 2 host targets. Valganciclovir, one of the drugs used in the study, was presented as a possible anti-SARS-CoV-2 therapeutic drug due to its high binding affinity to two wellestablished viral targets. The first target was PL pro , indispensable enzyme in viral replication; the second, RdRp, conserved Nsp12 in coronavirus, which is vital for its replication/transcription. Therefore, valganciclovir could be a significant antiviral drug to treat SARS-CoV-2. But there are no clinical reports on valganciclovir used to treat COVID-19 in addition to what has been reported about GCV. 141 Hence, its efficacy is yet to be confirmed as anti-SARS-CoV-2 therapeutic.

Tenofovir (TFV) (19) is another adenine analogue pointed as promising COVID-19 therapeutic (FIG. 4) , it is also called Tenofovir disoproxil fumarate or alafenamide Tenofovir (TAF).

Approved by the FDA in 2001, TFV is a prodrug used to treat HIV and cases of nucleoside resistance. 146 TFV is an analogue reverse-transcriptase inhibitor (NtRTI). Inside cells, TFV is phosphorylated and competes with deoxyadenosine 5'-monophosphate (d-AMP), thus preventing the formation of DNA. Once incorporated into a growing DNA strand, it causes premature termination of DNA transcription and prevents viral replication. 146, 147 Modelling and docking studies evaluated the antiviral effects of TFV and verified a strong bond to SARS-CoV-RdRp, which can disrupt this polymerase and terminate the viral infection. 7 However, in-vitro tests showed that TFV lacks apparent antiviral effect at concentrations inferior to 100 μM for SARS-CoV-2. 110 In spite of lukewarm in-vitro and in-silico outcomes, an ongoing clinical study on TFV (ChiCTR2000029468), expected to end in June 2020, aims at assessing the effect of the combination Tenofovir + emtricitabine (cytidine analogue) related to LPV/r in COVID-19 patients. 131 In addition to the efficacy of treatment, clinical trials can validate the prevalence of adverse effects related to the toxicity of TFV in patients. TFV is also a powerful nephrotoxic drug causing damage to proximal tubular cells. In spite of that, interrupting the treatment is sufficient to improve adverse effects, which makes monitoring of patients essential. 145 

Heterocyclic compounds with different heteroatoms such as Nitrogen, Sulphur and Oxygen can present different pharmacological properties. One such property is to serve as analogue of nitrogenous bases of nucleic acids, such as triazoles, which have a five-membered ring of two carbon atoms and three nitrogen atoms. This aromatic ring can assume two isometric forms, 1,2,3-triazole and 1,2,4-triazole. The former is stable under acid and basic conditions and becomes more reactive when binding to electronegative elements. 148, 149 Triazoles are important and stand out for their various biological activities, such as anticancer, 150 antituberculosis, 151 anti-inflammatory, 152 antimicrobial, 153 and antiviral. 154 Specifically for the latter action, triazole-based derivatives have shown promising invitro activity against coronavirus, probably by 3CL Pro inhibition. 155

Ribavirin (22) (FIG. 4) is a powerful triazole-based antiviral analogue to guanosine. It presents a wide range of pharmacological activities related to several viruses, for instance: herpes simplex virus, human immunodeficiency (HVI-1), influenza, respiratory syncytial (RSV) and hepatitis C. 149, 156 The drug was initially used in 1980 to treat syncytial virus in children, generally combined with Interferon (INF). However, ribavirin treatment presents undesirable adverse effects, like lowering of haemoglobin, which limit clinical use. 157 Its action mechanism relies on the inhibition of enzyme inosine monophosphate dehydrogenase, necessary in the synthesis of guanosine triphosphate, which prevents viral DNA and, mainly, RNA replication. The necessary concentration for in-vitro inhibition of RSV and influenza ranges from 3-10 μg/mL. 158 site similar to other SARS-PL pro inhibitors. The formation of hydrogen bonds and π-π stacking were also predicted. These findings suggest that ribavirin as a powerful PL pro inhibitor. Nonetheless, investigation on triazole derivatives for anti-SARS-CoV-2 therapy are still preliminary.

On the other hand, Favipiravir (FPV) (23) (FIG. 4) is a prodrug, approved in 2014 in Japan, to treat cases of influenza A and B that displayed resistance to first line drugs. It has provided results that indicate a promising character and is currently undergoing clinical trials against COVID-19. Its antiviral efficacy has also been investigated in different countries to fight Ebola and Lassa, for example. The molecular structure of the drug consists of a pyrazine heterocyclic ring with fluorine at 5-position, carboxamide at 3-position and a double bond between oxygen and Carbon 2, which renders its analogue to guanine (17). 162, 163 The metabolization of the prodrug into its active form, favipiravir-ribofuranosyl-5'-triphosphate, requires intracellular ribosylation and phosphorylation. 163 FPV therapeutic targets are RdRp enzymes, necessary in viral transcription and replication, and its inhibition blocks synthesis of viral RNA for a spectrum of viruses, including human coronavirus. A different investigation compared patients treated with FPV plus interferon inhalation to LPV/RTV. Patients under FPV therapy responded better to the progression of the disease with accentuated viral depuration. Also, the incidence of nausea and vomit was higher for LPV/RTV. 166 In addition to these clinical trials, the antiviral activity of FPV against SARS-CoV-2 was also evaluated but no clear antiviral effect was noted for doses lower than 100 μM. 110 An in-vitro study using molecular docking focused on the binding properties of SARS-CoV-2 protein structures to 61 antiviral agents, including oseltamivir. The study showed that 37 molecules form bonds to SARS-CoV-2 crystal proteins. However, data did not show oseltamivir as the best structure because Lopinavir, Asunaprevir and Remdesivir interacted with more than two protein structures in the virus. Hence, they are likely more promising than oseltamivir. 178 Notwithstanding, we suggest further look into oseltamivir against other enzyme targets since different studies achieved positive results regarding its use as anti-SARS-CoV-2.

Nelfinavir (27) (FIG. 5) is a safe anti-retroviral drug largely used for HIV-1 protease inhibition with strong in-vivo activity. 179 Generally, Nelfinavir is combined with other anti-retroviral medication as part of a highly active antiretroviral therapy (HAART) that reduces significantly the viral load by increasing cell number to 200 mm -3 CD4(+) lymphocytes. The drug is prescribed for children, young individuals, adults and pregnant women. 180, 181 Nelfinavir and its active metabolite M8 strongly bind to serum proteins, displaying optimal tissue distribution. A frequent adverse effect is light to moderate diarrhoea, reported for 15 to 20% of patients. 180 The SARS-CoV outbreak in several countries triggered the search for antiviral drugs active against the disease. Among the 24 drugs likely to inhibit SARS-CoV, nelfinavir stands out in all assays. 181 The mechanism of action suggested for nelfinavir involves preventing SARS-CoV replication after its entry in the host cell and disrupting virion production. Based on results from previous studies as well, nelfinavir was considered a likely therapy for COVID-19 after its indication for clinical trials as a promising anti-SARS drug.

Recently, 1,903 drugs were evaluated for their binding affinity to SARS-CoV-2 M pro . 182 Among the compounds, 15 drugs were selected based on the docking score and three-dimensional 

Atazanavir (28) (FIG. 5) is an antiretroviral drug protease inhibitor used to treat HIV infections with in-vitro inhibitory concentration of 2,6-5,3 nmol. Compared to other protease inhibitors, atazanavir has the advantage of allowing a daily posology regimen with a favourable metabolic profile and low frequency of adverse effects. 183, 184 Several HIV-1 resistant to protease inhibitors are still sensitive to in-vitro atazanavir, which is considered safe and well tolerated. 185 The atazanavir acts to inhibit HIV-1 protease, which is indispensable in the processing of polyproteins precursors of viral structures and prevents the formation of infectious and mature viral particles. 183 The good activities reported for this drug as well as the search for safe and fast therapy for 

Captopril (29) (FIG. 5) is an angiotensin-converting enzyme inhibitor (ACEi). It is a zinc metallopeptidases inhibitor that converts angiotensin-I into angiotensin-II, an essential function that regulates arterial pressure. It is predominantly indicated as vasodilator in patients with cardiac insufficiency. This drug was suggested as potential antibiotic capable of inhibiting zinc succinyls/dipeptidase by blocking its zinc catalytic center. 189, 190 Tolerance to captopril has been largely investigated; its single dose by mouth is well-established and confirms the pharmacological activity in the short term (10-30 minutes) at the cellular level. This capacity is related to captopril transport mainly through plasma proteins such as albumins with absorption rate between 70-75%.

Reported adverse effects are neutropenia, proteinuria, dysgeusia and cough, but less frequent for low doses. 189, 190 Some investigations have suggested captopril as possible COVID-19 treatment. Serafin et al. 100 indicated captopril as potential for inhibiting the bond between human SARS-CoV-2 and ACE-2 and reduce severe pneumonia symptoms.

In-silico studies using molecular docking were conducted with FDA-approved drugs capable of binding to the main active site in proteinase 3CL pro . 189 Two drugs were identified as ligands for the enzyme active site: captopril and disulfiram. The former binds to the active site at the same position of N3 inhibitor (a standard inhibitor that reacts irreversibly in the same site with 3CL pro Cys145). It is, thus, suggested that captopril binds to the same site of N3, obstructing the function of Cys145-His41 catalytic dyad. Captopril probably inhibits the enzyme in two stages. Initially, it establishes non-covalent bonds to sites in the enzyme targets, then, a reaction takes place between the critic groups, which results in a more stable inhibitor complex. The hypothesis is that captopril can bind covalently to 3CL pro Cys145. Although the potential of captopril on the enzyme has been demonstrated, therapeutic use against COVID-19 is controversial, once the drug induces overexpression of ACE-2 -the main receptor used by SARS-CoV-2 to entry the cells. Therefore, combination with other drugs, such as angiotensin-II receptor blockers, needs analysis to clarify the effects of captopril in COVID-19 treatment.

The cyclosporin A (CsA) (30) (FIG. 5) is isolated from the fungus Beauveria nivea and was approved for use by the FDA in 1983. This drug has been used for decades to prevent organ rejection and to treat T cell-associated autoimmune diseases such as Behcet's disease, psoriatic arthritis, lupus nephritis, rheumatoid arthritis, systemic lupus erythematosus or interstitial lung disease. Such drug exerts its immunosuppressive function and anti-inflammatory effects by inhibiting the transcription of genes required for T cell proliferation, notably interleukin-2. [191] [192] [193] Due to the severity of COVID-19, CsA can be potential to prevent hyperinflammation-induced lung injury. 194 In this regard, it is known SARS-CoV Nps1 induces the expression of interleukin-2 via nuclear factor of activated T cell (NF-AT) activation, 195 which can trigger the cytokine storm seen in patients with severe COVID-19 status. 138 Another advantage presented by CsA in relation to other antiinflammatory drugs is its already known anti-CoV action against all genus, including SARS-CoV, [195] [196] [197] at low and non-cytotoxic micromolar concentrations verified in cell culture assays. This antiviral property is thought to be mediated by the inhibition of cyclophilin-A-dependent viral assembly as well as inhibition of the NF-AT pathway or even by genetic or pharmacological specific inhibition of cyclophilin-D, hindering the viral replication. 195, 198 As already reported, SARS-CoV and SARS-CoV-2 are very similar (79.5% sequence identity). 17 

Teicoplanin (31) (FIG. 6) is an antibiotic used against gram-positive bacteria with 5 major compounds at different side chains. It prevents polymerization of peptidoglycans and inhibits the development of the cell-wall, thus prompting cell death. 203 It is a big molecule that has displayed antiviral activity on an early stage of the viral life cycle by inhibiting the low-pH cleavage of the viral spike protein by cathepsin L in the late endosomes thereby preventing release of viral RNA and replication. This compound has already shown inhibitory activity against Ebola virus, MERS-CoV and SARS-CoV. 203 Recent investigations have suggested teicoplanin as alternative treatment for COVID-19 after an in-vitro assay achieved IC 50 value of 1.66 µM, thus proving its efficacy against SARS-CoV-2.

These results need to be confirmed through randomized clinical trials, which are still to be conducted. 100, 204, 205 Using antibiotics to fight viruses, albeit completely ignored, can become useful to treat COVID-19. 206, 207 Some studies report the possibility of repurposing drugs like terconazole, which displayed good in-vitro results against MERS-CoV and SARS-CoV, 100 

Dasabuvir (32) (FIG. 6) is a drug from the naphthalene class and phenyl-naphthalene subclass due to the bond between its naphthalene ring and a phenyl group. Dasabuvir is a first line drug used as combined therapy for chronic hepatitis C. 208 Dasabuvir is a non-nucleoside inhibitor that binds to Nps5B (non-structural protein 5B -RdRp) and induces conformational change that makes RdRp incapable of elongating the viral RNA. 209 Repurposing of this drug can be useful as SARS-CoV-2 therapy due to its antiviral activity. 210 Dasabuvir was subjected to docking studies against SARS Briefly, Dasabuvir forms π-cation interactions with Lys31a (present in the ACE2), π-π interactions with Phe170b (S Protein residue) and hydrogen bonds to ACE2 residues Glu35a and Asp38a and Gly176b and Ser174b (S Protein residue). The authors highlight the importance of repurposing drugs as new therapeutic alternatives not only for the new coronavirus but for the next viral outbreaks.

Darunavir (33) (FIG. 6) is a benzene derivative that has been evaluated for repurposing against COVID-19. This drug is an antiviral used in the treatment of HIV-1 infections. It provides a great genetic barrier to resistance and is highly active against resistant strains of HIV-1 that are not susceptible to other protease inhibitors. 211 Darunavir is administered orally as pills or suspension and is often used with low doses of ritonavir as part of a combined ART protocol. 212 Its mechanism of actions works by protease inhibition. Darunavir establishes high affinity bonds to HIV-1 protease forming a stable complex, thereby selectively inhibiting polyprotein gag-pol coded by the virus. This prevents the formation of mature viral particles. 211 FDA-approved drugs against 3CL pro , RdRp, helicase, exonuclease 3′ a 5′, endoRNAse e 2′-O-ribose methyltransferase. Among the best drugs in the assay, darunavir was a surprise because, despite inhibiting viral proteinase, the study showed that it binds to the replication complex components of SARS-COV-2 with inhibitory potency Kd < 1000 nM. One example is RdRp, whose Kd value was 148.74 nM and exonuclease 3′ to 5′ with K d value of 195.73 nM.

A docking study was conducted by Sang et al. 215 as in-silico evaluation of anti-HIV drugs in their interaction capacity to proteinase 3CL pro . Results suggest that all drugs have higher binding affinity to SARS-CoV-2 3CL pro than to the homolog SARS-CoV proteinase. Among the evaluated drugs, indinavir and darunavir displayed the highest docking scores, therefore, they were subjected to molecular dynamic (MD) simulations, free binding energy calculations and Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) to detail molecular interactions between inhibitors and proteinase. The data suggest darunavir had better binding affinity to SARS-CoV-2 3CL pro with binding affinity of -10,24 kJ / mol. In addition, darunavir bind to SARS-CoV-2 3CL pro via 19 contact residues and to SARS-CoV 3CL pro via 17 residues. This difference explains the lower binding energy values between darunavir and SARS-CoV 3CL pro . It was also noted 5 hydrogen bonds between darunavir and SARS-CoV-2 3CL pro but none for indinavir and this proteinase. Because hydrogen bonds are important in the stability of the inhibitor-enzyme complex, darunavir is probably more promising against COVID-19. Finally, a different in-silico assay was conducted by Pant at al. 216 to assess a large variety of compounds (300) from several data banks and 66 potential compounds from FDA-approved drugs. The compounds were tested against SARS-COV-2 3CL pro . Darunavir was among the 20 best FDA-approved drugs, with a score of -7.208. All data collected from in-silico studies still require experimental studies to validate the anti-SARS-CoV-2 activity of darunavir.

A research conducted by Dyall et al. 99 performed a robust in-vitro assay and showed that the drug Dasatinib (34) (FIG. 6) , a kinase signalling inhibitor developed to treat human cancers, inhibited MERS-CoV and SARS-CoV, exhibiting EC 50 values 5.4 and 2.1, respectively. This study also revealed that kinase signalling may also be important for replication of this HCoVs. Nevertheless, the authors reported that dasatinib may be valuable against coronaviruses infections if a dosing regimen that minimizes immunotoxicity while still blocking viral replication can be defined. Results indicated this drug as a likely therapeutic alternative against SARS-CoV-2 infection. An in-silico study carried out by Qiao et al. 217 showed that dasatinib, among others, is one of the most promising drugs for the inhibition of SARS-CoV-2 3CL pro . More preclinical and clinical studies are required to prove whether dasatinib is really promising for COVID-19 patient treatment.

Imatinib (35) (FIG. 6) is an oral anticancer agent that inhibits the activity of some tyrosine kinases, most prominently the BCR-ABL fusion oncoprotein (whose overactivation can lead to chronic myeloid leukaemia, CML), c-kit (involved in gastrointestinal stromal tumours development), platelet-derived growth factor receptor (PDGFR), and the native ABL kinase, which has a ubiquitous expression and plays important roles in several biological processes. 218 In addition to this well-known antitumor effect, imatinib has also shown in-vitro antiviral properties against several virus, such as infectious bronchitis virus (a viral model for studying the role of tyrosine kinase activity during CoV infection), by interfering with virus-cell fusion, 219 and other RNA viruses including coxsackie virus, 220 hepatitis C virus, 221 Ebola, 222 among others, mainly by blocking viral entry or egress from the host cell. Besides, this drug showed activity against SARS-CoV and MERS-CoV, 223 both phylogenetically related to SARS-CoV-2. 24 In this regard, it is reported that imatinib has anti-CoV activity in two points of the virus life cycle. In the early phases of infection, it inhibits virion fusion with the endosome and subsequent release into the cytoplasm, thus preventing viral entry and viral replication via ABL-mediated cytoskeletal rearrangement. In a later phase of the infection, ABL2

protein expression, which is inhibited by this drug, enables SARS-CoV and MERS-CoV replication, which suggests that ABL2 is a new host cell protein required for viral growth. 223 Furthermore, evidences suggest that imatinib can modulate the immune response by sundry mechanisms, [224] [225] [226] for several diseases, such as rheumatoid arthritis, 227 asthma, 228 and Crohn's disease. 229 This information insinuates that such drug might perform its potentially beneficial immunomodulatory role as a treatment alternative for COVID-19 pneumonia. In addition, the use of imatinib as treatment appears to be reasonable from an economic point of view and its high availability in hospitals, 230 since this drug is well tolerated and the risk of severe adverse effects is relatively low, especially in short-term administration. 231 It is also recognized that adverse effects, mostly mild to moderate in intensity, will be easily controlled by dose reduction or discontinuation. 232 In light of this information, Tatar and Turhan 233 used the docking methodology to better understand the mechanism of inhibition of the SARS-CoV-2 N protein with 34 antiviral compounds.

Based on this study results, imatinib was one of the highly binding affinities performed against the aforementioned target, with the lowest micromolar Ki values among the compounds evaluated. In line with this study, an in-vitro research carried out by Weston et al. 234 found 17 FDA approved drugs that inhibited SARS-CoV-2 at non-cytotoxic concentrations. The authors indicate imatinib as one of the hits, since it exhibited IC 50 value of 3.24 μM. They subsequently determined the mechanism of action, demonstrating this drug inhibits fusion of CoVs with cellular membranes, precluding their entry. This result indicates imatinib use against SARS-CoV-2. However, its efficacy and safety need to be better confirmed in further preclinical and clinical trials in order of elect him as candidate drug in the treatment of COVID-19.

Synthesized for the first time by Jean Francois Rossignol in the beginning of the 1970s, the 2acetyloxy-N-(5-nitro-2-thiazolyl) benzamide, sold under the name nitazoxanide (NTZ) (36) (FIG. 6) , is the result of a structural modification in the antiparasitic niclosamide when a benzene ring is replaced with a nitrothiazole. 235, 236 Developed and sold as antiparasitic, NTZ is also a first line broad spectrum antiviral with good results against parainfluenza, coronavirus, rotavirus, hepatitis and other respiratory infections. [236] [237] [238] [239] Following oral administration, NTZ is absorbed in the intestine, where it is rapidly hydrolysed by plasma esterase into the active metabolite tizoxanide. 236 The mechanism of action of NTZ varies according to the pathogen. In relation to antiviral activity, NTZ blocks the maturation of the viral hemagglutinin at the post-translation stage in treatments against influenza. In treatments against HCV (hepatitis C), it activates protein kinase R (PKR), which leads to phosphorylation of the eukaryotic initiation factor-2α thereby preventing translation. 240 Cao et al. 241 conducted an in-vitro evaluation of NTZ against recombinant murine coronavirus expressing the firefly luciferase (MHV-2aFLS). The strand was pivotal to triage the 727 drugs with likely anti-CoV activity. The first assay resulted in 84 molecules among which was NTZ. The antiviral effect of NTZ verified for mouse astrocytoma (DBT) and fibroblasts (17Cl-1). 241 The DBT cells infected with MHV-2aFLS were treated with NTZ at 5 µM for 12 hours, after which the viral titer (TCID 50 ) was determined and viral N protein was subjected to Western blot. Results show the strong inhibitory effect of NTZ on the viral titer. 241 In-vitro studies on NTZ or its metabolite tizoxanide were also conducted to verify efficacy against different coronaviruses. The replication of Canine coronavirus (strain K378) in A72 cells, for instance, was blocked by the tizoxanide with IC 50 of 1 µg/mL. On the other hand, NTZ inhibited the viral N protein in bovine coronavirus L9 (βCoV-L9) and human enteric coronavirus 4408 (HECoV-4408) with approximate values of 0.3 µg/mL. 239, 241 NTZ is also responsible for inhibiting pro-inflammatory cytokines, such as TNF-α, IL-2, IL- Nitazoxanide (36) drugs.

More recently, molecules with a quinoline group have been widely investigated as treatment for the new coronavirus (SARS-CoV-2), such as Chloroquine (CQ) (37) and Hydroxychloroquine (HCQ) (38) (FIG. 7) that belong to the quinoline class and aminoquinoline subclass. Both are quickabsorption synthetic drugs approved to treat malaria (Plasmodium falciparum) by several regulating agencies in the world. CQ and HCQ are water soluble; the latter is more soluble due to presence of hydroxyl group. They are currently used to treat autoimmune diseases such as lupus erythematosus, antiphospholipid syndrome, rheumatoid arthritis as they have immunomodulatory and antithrombosis properties. [243] [244] [245] Therefore, these drugs could be useful against COVID-19 due to the elevated levels of cytokine caused by CoV infections in humans. 246 The mechanism of action of CQ for anti-malarial treatment is not entirely clear, but the interference with the digestion of haemoglobin by the parasite has been suggested. 245 HCQ has a similar mechanism, however, in regard to SARS-CoV-2, clinical trials showed it to be safer. [246] [247] [248] Therefore, HCQ, rather than CQ, is used against SARS-CoV-2. Recent studies report antiviral activity of CQ and HCQ as they impair viral entry and release in different in-vitro and in-vivo models. 244, 249 A factor that can also justify viral mechanisms is the aminoquinoline bioaccumulation in the tissues, as defended by Patil, Singhal & Masand. 243 A factor that facilitates viral replication is the acidic pH of endosomes, lysosomes and Golgi complex of the host. Thus, CQ is promising because it increases the pH of intracellular vacuoles, binds to the cellular receptors, changes the glycosylation and because of its selective and reversible immunomodulator effect on human CD4+ T cells. HCQ exerts similar mechanism of action: a)

increases the pH; b) modulation of activated immune cells; c) reduces the number of proinflammatory cytokine and other mediators to control inflammation. 243 It has also been suggested by Roldan et al. 244 a likely involvement of HCQ in iron homeostasis during SARS-CoV-2 infection, which is a similar mechanism to other viral infections in humans. [250] [251] [252] The little difference between the therapeutic and the toxic dose of CQ is also known, and poisoning is related to cardiovascular complications that can be fatal. Using either CQ or HCQ, then, requires strict prescription and self-medication is not advised. 249 Based on the RECOVERY data, it was concluded that HCQ is not effective in patients admitted with COVID-19. This highlights the importance of randomized clinical trials and the collection of clear data on the efficacy and safety of medications.

Ivermectin (39) (FIG. 7) is an FDA-approved broad-spectrum antiparasitic agent used in the treatment of tropical diseases, such as onchocerciasis, lymphatic filariasis, strongyloidiasis and lice.

There is also evidence of its effectiveness in the management of myiasis, trichinosis, malaria, leishmaniasis, trypanosomiasis, Chagas disease and schistosomiasis as well as bed bugs, inflammatory skin lesions, epilepsy, neurological diseases, tuberculosis and some cancers. 266 It is known that ivermectin is capable of inhibiting the bond between a virus and the nuclear transport mediated by the superfamily of importin proteins (IMP α/β1) 267 Based on the fact that SARS-CoV-2 is a RNA virus deeply related to SARS-CoV, studies on SARS-CoV proteins have revealed a potential role for IMP α/β1 during infection in signal-dependent nucleocytoplasmic shutting of the SARS-CoV nucleocapsid protein. 273 Furthermore, the SARS-CoV accessory protein ORF6 has been shown to antagonize the antiviral activity of the STAT1 transcription factor by sequestering IMP α/β1 on the rough ER/Golgi membrane. 274 Considering the ivermectin nuclear transport inhibitory activity, such drug is widely believed as a promising therapeutic approach against SARS-CoV-2.

Recently, Caly et al. 275 A different mechanism of action that consolidates the use of ivermectin against COVID-19 is its immunomodulatory property. The inflammatory response (proinflammatory cytokine) is exaggerated in patients with the extreme case of the disease, which is likely explained by the hypoxiainducible factor (HIF-1α) that is activated by the virus when no inhibitory medication is administered.

This understanding can be explained by the study conducted by Kosyna et al. 276 , whose lab tests with and without ivermectin aimed to examine whether the properties of the bond between HIF-1α and IMP α/β1 and between HIF-1 and nuclear localization signals were affected by the hypoxia mechanism on the cellular level. The authors concluded that ivermectin inhibited both IMP α/β1 and HIF-1α.

Regarding This hinders its indication and clinical decisions. Thus far, data indicate ivermectin is useful at the early stages of the disease, even the epidemiologic profile of COVID-19 shows significant differences regarding the age of patients for the affected countries and patients with comorbidity. 279 Therefore, large scale randomized clinical trials are necessary to standardize clinical, laboratory and image evaluations, as well as combined drug therapy with vitamins and zinc, for example. 280 Financially, ivermectin is inexpensive and its doses and protocols are well established for different purposes. In addition, this drug has little side effects. 281

Indole, also named benzo [b] pyrrole, is a planar bicyclic heteroaromatic, whose ten π electrons move across its structure making this chemical group behave as a weak base. 282, The indole ring is the most abundant heterocyclic in nature and is commonly found in biologically active natural products, such as vegetables and seafood. It is also present in the structure of the essential amino acid tryptophan, which interferes with protein synthesis and with the regulation of physiological mechanisms such as precursors for serotonin and vitamin B3. 283 288 and adding the indole ring to spirothiazolidinones conducted to better influenza A/H3N2 inhibition. 289 Now, the antiviral activity of indole and its derivatives for COVID-19 therapy is supposed.

Arbidol (40) is also a promising drug to fight COVID-19 (FIG. 7) . This drug is classified as antiviral and has been used for 25 there is high expression of ECA2, identified as human receptor for virus entry. 290 Notwithstanding, a different clinic trial concluded that Arbidol monotherapy is best for the patient than LPV/RTV. 291 Despite the results, both investigations recognize their own limitations due to small cohort size and lack of placebo-control group. According to the authors, these limitations are inherent to pandemic times when placebo-control groups are difficult to conduct due to life-threatening conditions.

Most studies with Arbidol use 200 mg/3*day 164, 290, 291 following the Chinese guidelines.

Previous investigations on the pharmacokinetics of Arbidol in healthy Chinese patients showed that a single 800 mg oral dose is sufficient for Cmax de ~4,1μM. 293 This value was obtained through invitro assays that pointed the drug as effective and promising against SARS-CoV-2. Hence, clinical trials are still necessary to confirm the efficacy of Arbidol at elevated doses to treat COVID-19. 293

Rizatriptan (RZT) (41) (FIG. 7) is used to treat migraine and is a selective receptor of serotonin (5-HT) type 1B and 1D, structurally and pharmacologically related to other selective antagonists at these receptors. 294 Its structure is based on an indole ring replaced with methyltriazole at 5-position and unsubstituted ethanamine replaced with methyl at 3-position, the substitution sites are the same of melatonin (MLT). After virtual triage through molecular dock at spike-ACE2 interface, ligations π-cation, interactions π-π and hydrogen bonds were identified between RZT and the SARS-CoV-2 protein complex. As one of the outstanding compounds in the analysis, in-vitro tests are still necessary. 187 It is noteworthy that overdosing of the drug can trigger dizziness, fainting, cardiac issues, hypertension, bradycardia and vomiting. Despite the safety of the drug in regular doses, there are no reports on either in-vitro or in-vivo tests to support the theoretical data and the antiviral action thus far.

One last indole derivative that could be repurposed to treat COVID-19 is melatonin (MLT) (42) (FIG. 7) . MLT is classified as a hormone and nutraceutical, as it is naturally produced by the pineal gland and released into the bloodstream. It regulates the sleep-wake cycle as well as our mood, learning and memory, fertility, reproduction and the immune system. From a chemical perspective, it is an indole derivative with a methoxy group at 5-position and one ethylacetamide at 3-position. 295 Regarding its antiviral potential, MLT acts indirectly through anti-inflammatory, antioxidant and immune modulating activities. 296 An investigation with murine infected with Semliki Forest Virus (SFV) and West Nile Virus (WNV) showed the efficiency of MLT in reducing mortality rates for these viruses as well as in reducing the levels of pro-inflammatory cytokines. 297 The anti-inflammatory and antioxidant properties of MLT point to its antiviral effects in humans. 298 Based on computational data, Zhou et al. 299 suggested using combined medication to fight SARS-CoV-2. One such combination involves MLT plus mercaptopurine in synergic action against the following targets: PL pro , ACE2, c-Jun signal and anti-inflammatory vias. Therefore, experimental studies on modifications of ACE2 pathways caused by MLT are useful to understand this drug. 299 On the other hand, it has been suggested that using this neuro-hormone can mitigate the extreme form of the disease, the acute respiratory syndrome that has caused most deaths by SARS-CoV-2 cases.

Despite its safety for humans, the lack of data on the relevance of its use for COVID-19 patients 

Emetine (43) is an approved anti-protozoal drug used against amebae with reported inhibitory activity for enterovirus infections, 301 Zika virus and Ebola by interfering with the process of viral replication and entry in host cells. 302 Emetine is an isoquinoline alkaloid that presents 4 methoxy groups in its structure (FIG. 7) . Studies also confirm emetine has in-vitro activity against coronaviruses, including SARS-CoV and MERS-CoV. 99 assays to clarify the activity of these drugs and the mechanism involved in the antiviral action of emetine both in isolation and combined to other drugs.

Another alkaloid candidate to repurpose against COVID-19 is homoharringtonine (HHT) (44) (FIG. 8) . HHT is an FDA-approved drug in semi-synthetic form known as omacetaxine. This drug displays antitumoral activity in the treatment of myeloid chronic leukaemia. The mechanism of action implicates the ribosomal bond to prevent protein translation. In addition to antitumor activity, there are data in the literature that describe antiviral activity of HHT against several types of viruses including CoVs. 304, 305 A recent in-vitro evaluation of anti-SARS-CoV-2 activity displayed EC 50 of 2.10 µM. However, the mechanism of action is not yet clear, which demands further investigation on ideal doses of HHT to achieve the clinical results expected of a COVID-19 therapeutic drug. 110

The first reports on tetraethylthiuram disulfide, disulfiram (DSF) (45) (FIG. 8) , date back to 1881. However, only in the 1940s that DSF would become popular when it was discovered that it could form copper chelates which favoured the death of micro-organisms and enabled treatment of intestinal parasites. [306] [307] [308] In 1945, DSF alcohol sensitivity was discovered accidentally and it was soon used in the clinical treatment of alcohol dependence. 309, 310 DSF is used to treat alcohol dependence because it irreversibly inhibits the acetaldehyde dehydrogenase enzyme and modifies cysteine residues in its active site. This change prompts the formation of a disulphide bond between two cysteine residues in the active site. 311 DSF effectiveness is based on its similarly to several proteins yielding a range of biological activities, such as antitumoral, 312, 313 antimicrobial, 310 and anti-SARS and MERS-CoV. 314 Adding to the list of drugs to be repurposed against SARS-CoV-2, recent studies indicate that DSF is able to inhibit other enzymes, such as methyltransferase, urease and kinase, all by reacting with important cysteine residues that suppress the natural cycle of the enzymes, suggesting broad-spectrum characteristics. 312, 314 CoVs have two viral enzymes, M pro and PL pro , that are cysteine protease involved in the formation of structural and non-structural proteins that constitute the viruses and favour control of host cells. 315 Different assays, such as proteolytic and binding synergy assays, were also conducted and described. 314 Although outcomes indicate DSF for anti-MERS-CoV and anti-SARS-CoV therapy, to the present date (15 th June 2020), no other article was published claiming the availability of the compound as promising anti-SARS-CoV-2.

Recently, an announcement was published on the Oxford University website on the results of one Randomized Evaluation of COVID-19 therapy. 317 More specifically, the study focused on dexamethasone (46), a corticosteroid with fluorine at 9-position (FIG. 8) . The drug is mostly used as anti-inflammatory, which works by inhibiting vasodilation, reducing leukocyte migration to the inflammation site and increasing vascular permeability. 318 

Immunotherapy is an effective intervention in viral infections. Most attempts at immunotherapy were successful in fighting viruses similar to SARS-CoV-2. The principal methods include vaccine, neutralizing antibodies (nAbs) candidates and convalescent plasma. 35, 61, 67, 68, 156, 319, 320 In addition, according to the evidences from viral infections (Ebola, Influenza, SARS and MERS), immunotherapeutic interventions can reduce viral load and mortality rate of patients. 321, 322 Development of either monoclonal (mAbs) or polyclonal (pAbs) neutralizing antibodies is a commonly adopted immunotherapeutic alternative due to its specificity, purity, low contamination by blood-transmitted pathogens and relative safety. However, there are limitations to the use of nAbs once its development and large-scale production for clinical use are a complex, expensive and slow process. 321 Promising scientific investigations have suggested using mAbs or pAbs as prophylactic and therapeutic measures against influenza 323 and HCoVs, such as MERS-CoV 324 and SARS-CoV. 325 Targets reported as promising for HCoVs immunotherapy were cytokine, 326 S1-receptor-binding domain (S1-RBD), S1 N-terminal domain (S1-NTD) and some other region of subunit S2 in order to block the RBDs bonds to their respective receptors and to interfere either with S2-mediated membrane fusion or with the entry in the host cells, thus inhibiting infection. 327 These researchers have encouraged the development of nAbs with cross reactivity potential and/or cross neutralization effect on SARS-CoV-2 infections, as shown by Tian et al. 328 Data suggest that mAb CR3022 can be developed as therapeutic candidate, either isolated or combined with neutralizing antibodies to prevent and treat COVID-19, given that it could potently form bonds with SARS-CoV-2 RBD (KD of 6.3 nM). A different study by Wang et al. 329 reported the discovery of a human mAb (47D11) that promoted cross neutralization of SARS-CoV and SARS-CoV-2 in a culture of cells through an independent receptor-binding inhibition mechanism that targets a conserved epitope on the spike HCoVs RBD mentioned above.

It is also reported the on-going investigation of convalescent plasma or immunoglobulin as last resource to improve the survival rate of patients with several viral infections such as H 5 N 1 avian influenza, 330 334 A possible explanation for the efficacy of convalescent plasma is that immunoglobulin antibodies in the plasma of recovered patients can suppress viremia. 156 Shen et al. 335 reported that five patients with extreme symptoms of COVID-19 received blood transfusion containing convalescent plasma with specific SARS-CoV-2 antibodies. After a series of blood transfusions, the improvement in clinical status of patients was observed. Viral loads also decreased and became negative within 12 days after the transfusion, and SARS-CoV-2-specific ELISA and nAbs titers increased following the transfusion. In spite of the limited sample, the authors concluded that convalescent plasma transfusion benefited patients infected with SARS-CoV-2. Therefore, testing safety and efficacy of transfusing convalescent plasma in patients infected with SARS-CoV-2 can be of value. 319, 336 Among the modalities of immunotherapy, vaccines are expected to be more promising, hence the global engagement in their production. Over the last decade, the scientific community and the vaccine industry had to answer urgently to the epidemics of H1N1, Ebola, Zika and, more recently, SARS-CoV-2. Vaccine development is an expensive and slow process with high risks of failure, which often motivate developers to follow a linear sequence of steps with several breaks for data analysis and fabrication processes. Therefore, it is fundamental that vaccines be developed through faithful methods even if it takes longer to move them onto clinical trials or to make a large number of doses available, a challenge during a pandemic. 337 Developing efficient vaccines for SARS-CoV-2 will be essential to reduce the severity of the disease, viral shedding and transmission to control future outbreaks. Prior to the COVID-19

pandemic, multiple strategies were used to generate vaccines for the first HCoVs (SARS-CoV and MERS-CoV). 338 Several studies related to SARS-CoV vaccine production targeting the protein S, due to its function in the receptor binding and fusion to the host membrane, were successful in animal tests against that coronavirus. 339-341 These vaccines employed live-attenuated virus vaccines, killed virus, DNA vaccines and viral vector vaccines. Theoretically, these techniques could be applied to develop SARS-CoV-2 vaccines given their similarities from both the genomic perspective and the mechanisms employed in the invasion and infection of host cells. 326 Gao et al. 342 promoted the pilotscale production of a purified inactivated SARS-CoV-2 virus vaccine candidate (PiCoVacc), which induced SARS-CoV-2-specific nAbs in mice, rats and non-human primates. In addition, three immunizations using two different doses (3 μg or 6 μg per dose) in macaques provided partial or complete protection against the SARS-CoV-2 challenge, respectively, without observable antibodydependent enhancement of infection. These data reinforce the use of PiCoVacc in the next steps of clinical trials targeting SARS-CoV-2 still for the present year.

Given the magnitude of the COVID-19 pandemic, it has become indispensable to work as fast as possible to develop vaccines for global distribution. However, protocols are necessary to safekeep the population's health. Hence, before allowing human testing of COVID-19 vaccines, regulatory organizations must evaluate their safety against a series of virus strains and more than one animal model. They also must demand preclinical evidences that experimental vaccines prevent infectioneven if it means waiting weeks or months for models to become available. This is time well-spent, once testing vaccines without investing the due amount of time to completely understand the risks can lead to setbacks for current and future pandemics. 343 repurposing potential relies on the mechanism for other viruses, such as Hepatitis C, by inducing conformational changes that compromise RdRp activity. It was also possible to identify benzene derivatives used to treat cancer (Dasatinib and Imatinib) and one antiviral (Darunavir), but predominant in-silico and some in-vitro outcomes demand more conclusive studies. Representative of benzoic derivatives, NTZ displayed significant inhibitory activity against pro-inflammatory cytokines, which can benefit control of ARDS, in spite of an unclear mechanism against SARS-CoV-2.

Quinoline derivatives, HCQ and CQ, were some of the first drugs investigated. After several in-silico, in-vitro and in-vivo assays, based on results presented by RECOVERY to the present date, unfortunately, these drugs were proven ineffective in hospitalized COVID-19 patients. Ivermectin represents macrolide derivatives and is suggested as promising due to both immunostimulatory activity and inhibitory activity on nuclear transport when administered at the early stages of the disease. Among indole derivatives, Arbidol was pointed out as useful for reducing viral binding and releasing of intracellular vacuoles that contain the virus. Nonetheless, clinical trials are still necessary after dose adjustment for better outcomes. Both indole derivatives (emetine and HHT), in spite of promising results, were only submitted to in-silico and in-vitro tests, thus demanding further investigation on their toxicity and mechanism of control.

Hence, the currently available data on the classes of drugs investigated here revealed that drugs were considered promising mainly after in-silico tests only. In fact, the inefficacy of some of these drugs became evident after in-vitro or in-vitro tests, as CQ and HCQ, whose clinical trials failed to confirm the so-expected anti-SARS-CoV-2 activity. It is necessary to highlight the importance of clinical trials with drugs considered promising in theoretical studies, with due calm and openness to question and refute hypotheses, in the absence of scientific evidence to support their use to treat COVID-19. Similarly, the careful analysis of practices involving patients with the extreme form of the disease is also important to identify new alternatives, such as the results recently published by RECOVERY on dexamethasone. It is also expected that detailed clinical trials are conducted with some of the drugs described in this article as potential anti-SARS-CoV-2, for instance Sofosbuvir, 

Origin and evolution of pathogenic coronaviruses

The COVID-19 vaccine development landscape

SARS-CoV-2 Vaccines: Status Report

Recent discovery and development of inhibitors targeting coronaviruses

Analysis of therapeutic targets for SARS-CoV-2 and discovery of potential drugs by computational methods

Drug Repurposing for Viral Infectious Diseases: How Far Are We?

Tenofovir against SARS-CoV-2 RNA dependent RNA polymerase (RdRp): A molecular docking study

Virtual screening and repurposing of FDA approved drugs against COVID-19 main protease

Baricitinib as potential treatment for 2019-nCoV acute respiratory disease

Remdesivir and SARS-CoV-2: Structural requirements at both nsp12 RdRp and nsp14 Exonuclease active-sites

Coronaviruses -drug discovery and therapeutic options

Development of One-Step, Real-Time, Quantitative Reverse Transcriptase PCR Assays for Absolute Quantitation of Human Coronaviruses OC43 and 229E

Coronavirus as a possible cause of severe acute respiratory syndrome

Isolation of a Novel Coronavirus from a Man with Pneumonia in Saudi Arabia

A Review of Coronavirus Disease-2019 (COVID-19)

Emergence of Novel Coronavirus 2019-nCoV: Need for Rapid Vaccine and Biologics Development

A pneumonia outbreak associated with a new coronavirus of probable bat origin

World Health Organization. Coronavirus disease (COVID-19) pandemic

Advances in Virus Research

COVID-19: A promising cure for the global panic

Genotype and phenotype of COVID-19: Their roles in pathogenesis

Molecular Evolution of Human Coronavirus Genomes

Recent progress and challenges in drug development against COVID-19 coronavirus (SARS-CoV-2) -an update on the status

Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding

Structure analysis of the receptor binding of 2019-nCoV

Mechanistic insights into the effect of humidity on airborne influenza virus survival, transmission and incidence

Visualizing Speech-Generated Oral Fluid Droplets with Laser Light Scattering

Pitfalls of judgment during the COVID-19 pandemic

A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster

Temporal profiles of viral load in posterior oropharyngeal saliva samples and serum antibody responses during infection by SARS-CoV-2: an observational cohort study

Origin of viruses: primordial replicators recruiting capsids from hosts

The Coronavirus Spike Protein Is a Class I Virus Fusion Protein: Structural and Functional Characterization of the Fusion Core Complex

SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor

Renin-Angiotensin-Aldosterone System Inhibitors in Patients with Covid-19

Renin-angiotensin-aldosterone system and COVID-19 infection

COVID-19 infection: Origin, transmission, and characteristics of human coronaviruses

Review of the Clinical Characteristics of Coronavirus Disease 2019 (COVID-19)

Mild or Moderate Covid-19

The origin, transmission and clinical therapies on coronavirus disease 2019 (COVID-19) outbreakan update on the status

Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China

Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

Clinical Characteristics of Coronavirus Disease 2019 in China

Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study

Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection?

Comorbidities and multi-organ injuries in the treatment of COVID-19

The vasoprotective axes of the renin-angiotensin system: Physiological relevance and therapeutic implications in cardiovascular, hypertensive and kidney diseases

SARS-CoV-2 and viral sepsis: observations and hypotheses

Novel Coronavirus Infection (COVID-19) in Humans: A Scoping Review and Meta-Analysis

Sex-Specific SARS-CoV-2 Mortality: Among Hormone-Modulated ACE2 Expression, Risk of Venous Thromboembolism and Hypovitaminosis D

Probiotics and COVID-19: one size does not fit all

Clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study

Pathological findings of COVID-19 associated with acute respiratory distress syndrome

Liver injury in COVID-19: management and challenges

Endothelial cell infection and endotheliitis in COVID-19

Comorbidities and multi-organ injuries in the treatment of COVID-19

Coronavirus infections and immune responses

Longitudinal characteristics of lymphocyte responses and cytokine profiles in the peripheral blood of SARS-CoV-2 infected patients

Reducing mortality from 2019-nCoV: host-directed therapies should be an option

Ribavirin and interferon alfa-2a for severe Middle East respiratory syndrome coronavirus infection: a retrospective cohort study

Coronavirus membrane fusion mechanism offers a potential target for antiviral development

Pharmacological Therapeutics Targeting RNA-Dependent RNA Polymerase, Proteinase and Spike Protein: From Mechanistic Studies to Clinical Trials for COVID-19

Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor

Structural basis of receptor recognition by SARS-CoV-2

A possible strategy to fight COVID-19: Interfering with spike glycoprotein trimerization

The Spike Protein of the Emerging Betacoronavirus EMC Uses a Novel Coronavirus Receptor for Entry, Can Be Activated by TMPRSS2, and Is Targeted by Neutralizing Antibodies

Evidence that TMPRSS2 Activates the Severe Acute Respiratory Syndrome Coronavirus Spike Protein for Membrane Fusion and Reduces Viral Control by the Humoral Immune Response

Contributes to Virus Spread and Immunopathology in the Airways of Murine Models after Coronavirus Infection

Simultaneous Treatment of Human Bronchial Epithelial Cells with Serine and Cysteine Protease Inhibitors Prevents Severe Acute Respiratory Syndrome Coronavirus Entry

Efficient Activation of the Severe Acute Respiratory Syndrome Coronavirus Spike Protein by the Transmembrane Protease TMPRSS2

Transmembrane Serine Protease Is Linked to the Severe Acute Respiratory Syndrome Coronavirus Receptor and Activates Virus Entry

Protease inhibitors targeting coronavirus and filovirus entry

Structural basis of SARS-CoV-2 3CLpro and anti-COVID-19 drug discovery from medicinal plants

Structure of the RNA-dependent RNA polymerase from COVID-19 virus

Structural basis for inhibition of the RNA-dependent RNA polymerase from SARS-CoV-2 by remdesivir

Structure of Mpro from SARS-CoV-2 and discovery of its inhibitors

Efficiency of Incorporation and Chain Termination Determines the Inhibition Potency of 2′-Modified Nucleotide Analogs against Hepatitis C Virus Polymerase

Protective effect and potential mechanisms of Wei-Chang-An pill on high-dose 5-fluorouracil-induced intestinal mucositis in mice

Higher order structures in purine and pyrimidine metabolism

Human pyrimidine nucleotide biosynthesis as a target for antiviral chemotherapy

Pyrrolopyrimidines: An update on recent advancements in their medicinal attributes

Synthesis and evaluation of anti-tumor activity of novel triazolo[1,5-a] pyrimidine on cancer cells by induction of cellular apoptosis and inhibition of epithelial-to-mesenchymal transition process

A facile one pot synthesis of novel pyrimidine derivatives of 1,5-benzodiazepines via domino reaction and their antibacterial evaluation

High antiparasitic activity of silver complexes of 5,7-dimethyl-1,2,4-triazolo[1,5 a]pyrimidine

New carbocyclic N6-substituted adenine and pyrimidine nucleoside analogues with a bicyclo[2.2.1]heptane fragment as sugar moiety; synthesis, antiviral, anticancer activity and X-ray crystallography

New prodrugs of two pyrimidine acyclic nucleoside phosphonates: Synthesis and antiviral activity

5-Fluorouracil upregulates cell surface B7-H1 (PD-L1) expression in gastrointestinal cancers

A new animal model of intestinal mucositis induced by the combination of irinotecan and 5-fluorouracil in mice

5-Fluorouracil in combination with deoxyribonucleosides and deoxyribose as possible therapeutic options for the Coronavirus, COVID-19 infection

The safety and efficacy of gemcitabine for the treatment of bladder cancer

Depletion of SIRT7 sensitizes human non-small cell lung cancer cells to gemcitabine therapy by inhibiting autophagy

Gemcitabine for recurrent ovarian cancer -a systematic review and meta-analysis

Repurposing of Clinically Developed Drugs for Treatment of Middle East Respiratory Syndrome Coronavirus Infection

Drug repositioning is an alternative for the treatment of coronavirus COVID-19

An Efficient Synthesis of Baricitinib

Janus Kinase inhibitor Baricitinib Modulates human innate and adaptive immune system

In Vivo Antitumor Activity of SU11248, a Novel Tyrosine Kinase Inhibitor Targeting Vascular Endothelial Growth Factor and Platelet-derived Growth Factor Receptors: Determination of a Pharmacokinetic/Pharmacodynamic Relationship

The EGF receptor family as targets for cancer therapy

Janus kinase inhibitor baricitinib is not an ideal option for management of COVID-19

Protection against filovirus diseases by a novel broad-spectrum nucleoside analogue BCX4430

Galidesivir limits Rift Valley fever virus infection and disease in Syrian golden hamsters

Therapeutic options for the 2019 novel coronavirus (2019-nCoV)

New Nucleoside Analogues for the Treatment of Hemorrhagic Fever Virus Infections

Remdesivir, lopinavir, emetine, and homoharringtonine inhibit SARS-CoV-2 replication in vitro

Genotype and Subtype Profiling of PSI-7977 as a Nucleotide Inhibitor of Hepatitis C Virus

Selected nucleos(t)ide-based prescribed drugs and their multi-target activity

Mechanism of Activation of PSI-7851 and Its Diastereoisomer PSI-7977

Evaluation of Sofosbuvir (β-D-2′-deoxy-2′-α-fluoro-2′-β-Cmethyluridine) as an inhibitor of Dengue virus replication

Yellow fever virus is susceptible to sofosbuvir both in vitro and in vivo

The FDA-approved drug sofosbuvir inhibits Zika virus infection

Beyond Members of the Flaviviridae Family, Sofosbuvir Also Inhibits Chikungunya Virus Replication

Sofosbuvir as Repurposed Antiviral Drug Against COVID-19: Why Were We Convinced to Evaluate the Drug in a Registered/Approved Clinical Trial

Antiviral β-L-nucleosides specific for hepatitis B virus infection. In: Frontiers in Viral Hepatitis

Treatment of chronic hepatitis B: focus on telbivudine

Safety and efficacy of telbivudine for the treatment of chronic hepatitis B. Ther Clin Risk Manag

9-trisubstituted-9H-purine)-8-chalcone derivatives as potent anti-gastric cancer agents: Design, synthesis and structural optimization

Novel phosphodiesterases inhibitors from the group of purine-2,6-dione derivatives as potent modulators of airway smooth muscle cell remodelling

Novel butanehydrazide derivatives of purine-2,6-dione as dual PDE4/7 inhibitors with potential anti-inflammatory activity: Design, synthesis and biological evaluation

The purines: Potent and versatile small molecule inhibitors and modulators of key biological targets

synthesis and biological evaluation of novel HIV-1 protease inhibitors with pentacyclic triterpenoids as P2-ligands

Seley-Radtke, Design, synthesis and evaluation of a series of acyclic fleximer nucleoside analogues with anti-coronavirus activity

Remdesivir in COVID-19: A critical review of pharmacology, pre-clinical and clinical studies

The epidemiology, diagnosis and treatment of COVID-19

Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys

A Randomized, Controlled Trial of Ebola Virus Disease Therapeutics

Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses

Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against MERS-CoV

First Case of 2019 Novel Coronavirus in the United States

Compassionate Use of Remdesivir for Patients with Severe Covid-19

Pharmacologic Treatments for Coronavirus Disease 2019 (COVID-19)

Oral Ganciclovir for Patients with Cytomegalovirus Retinitis Treated with a Ganciclovir Implant

DrugBank 5.0: a major update to the DrugBank database

Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study

Incidence, Risk Factors, and Outcome of Cytomegalovirus Infection and Disease in Patients Receiving Prophylaxis with Oral Valganciclovir or Intravenous Ganciclovir after Umbilical Cord Blood Transplantation

Pharmacokinetics of Ganciclovir after Oral Valganciclovir versus Intravenous Ganciclovir in Allogeneic Stem Cell Transplant Patients with Graft-versus-Host Disease of the Gastrointestinal Tract

The First 75 Days of Novel Coronavirus (SARS-CoV-2) Outbreak: Recent Advances, Prevention, and Treatment

Tenofovir Disoproxil Fumarate

3-Triazole-containing hybrids as leads in medicinal chemistry: A recent overview

Medicinal attributes of 1,2,3-triazoles: Current developments

Synthesis and anticancer activity of long chain substituted 1,3,4-oxadiazol-2-thione, 1,2,4-triazol-3-thione and 1,2,4-triazolo[3,4-b]-1,3,4-thiadiazine derivatives

Chemical synthesis and biological evaluation of triazole derivatives as inhibitors of InhA and antituberculosis agents

Synthesis, antiinflammatory and analgesic activity of 2-[4-(substituted benzylideneamino)-5-(substituted phenoxymethyl)-4H-1,2,4-triazol-3-yl thio] acetic acid derivatives

Synthesis and biological evaluation of some novel triazol-3-ones as antimicrobial agents

Design, synthesis, antiviral and cytostatic activity of ω-(1H-1,2,3-triazol-1-yl)(polyhydroxy)alkylphosphonates as acyclic nucleotide analogues

Synthesis, biological evaluation and molecular modeling of a novel series of fused 1,2,3-triazoles as potential anti-coronavirus agents

Treatment options for COVID-19: The reality and challenges

Compounds with Therapeutic Potential against Novel Respiratory

Ribavirin in the treatment of SARS: A new trick for an old drug?

Inhibition of novel β coronavirus replication by a combination of interferon-α2b and ribavirin

Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro

Anti-HCV, nucleotide inhibitors, repurposing against COVID-19

Ebola virus dynamics in mice treated with favipiravir

Favipiravir (T-705), a broad-spectrum inhibitor of viral RNA polymerase

Favipiravir versus Arbidol for COVID-19: A Randomized Clinical Trial. medRxiv [Epub ahead of print

A Possible Pharmaceutical Treatment for COVID-19

Experimental Treatment with Favipiravir for COVID-19: An Open-Label Control Study. Engineering

an antiviral for COVID-19?

Covid-19 -The Search for Effective Therapy

Coronavirus disease 2019 (COVID-19): current status and future perspectives

Role of lopinavir/ritonavir in the treatment of SARS: initial virological and clinical findings

Improves Outcome of MERS-CoV Infection in a Nonhuman Primate Model of Common Marmoset

Combination therapy with lopinavir/ritonavir, ribavirin and interferon-alpha for Middle East respiratory syndrome: a case report

A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19

Triple combination of interferon beta-1b, lopinavirritonavir, and ribavirin in the treatment of patients admitted to hospital with COVID-19: an openlabel, randomised, phase 2 trial

Molecular Modeling Evaluation of the Binding Abilities of Ritonavir and Lopinavir to Wuhan Pneumonia Coronavirus Proteases

Oseltamivir Treatment of Influenza in Children

Therapeutic Management of COVID-19 Patients: A systematic review

In silico studies on therapeutic agents for COVID-19: Drug repurposing approach

Synergistic antiviral effect of Galanthus nivalis agglutinin and nelfinavir against feline coronavirus

HIV protease inhibitor nelfinavir inhibits replication of SARS-associated coronavirus

Nelfinavir was predicted to be a potential inhibitor of 2019-nCov main protease by an integrative approach combining homology modelling, molecular docking and binding free energy calculation

Atazanavir for the Treatment of Human Immunodeficiency Virus Infection

Influence of atazanavir on the pharmacodynamics and pharmacokinetics of gliclazide in animal models

Therapy with atazanavir plus saquinavir in patients failing highly active antiretroviral therapy: a randomized comparative pilot trial

Predicting commercially available antiviral drugs that may act on the novel coronavirus (SARS-CoV-2) through a drug-target interaction deep learning model

Déjà vu: Stimulating open drug discovery for SARS-CoV-2

State-of-the-art tools unveil potent drug targets amongst clinically approved drugs to inhibit helicase in SARS-CoV-2

FDA-approved thiolreacting drugs that potentially bind into the SARS-CoV-2 main protease, essential for viral replication

Cyclosporin A and cardioprotection: from investigative tool to therapeutic agent

Modulation of innate immunity by cyclosporine A

The Use of Cyclosporine A in Rheumatology: a 2016 Comprehensive Review

Cyclosporine A: a valid candidate to treat COVID-19 patients with acute respiratory failure?

The SARS-Coronavirus-Host Interactome: Identification of Cyclophilins as Target for Pan-Coronavirus Inhibitors

Cyclosporin A inhibits the replication of diverse coronaviruses

Human coronavirus NL63 replication is cyclophilin A-dependent and inhibited by non-immunosuppressive cyclosporine A-derivatives including Alisporivir

Cyclophilins and cyclophilin inhibitors in nidovirus replication

Identification of antiviral drug candidates against SARS-CoV-2 from FDA-approved drugs

Cyclosporin A is a potential inhibitor of SARS-CoV-2. ResearchGate (preprint)

Cyclosporine therapy in cytokine storm due to coronavirus disease 2019 (COVID-19)

Clinically Significant Drug Interactions with Cyclosporin

Glycopeptide Antibiotics Potently Inhibit Cathepsin L in the Late Endosome/Lysosome and Block the Entry of Ebola Virus, Middle East Respiratory Syndrome Coronavirus (MERS-CoV), and Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV)

Discovery and development of safe-in-man broadspectrum antiviral agents

Teicoplanin: an alternative drug for the treatment of COVID-19?

Fighting viruses with antibiotics: an overlooked path

Current epidemiological and clinical features of COVID-19; a global perspective from China

Pharmacokinetics and safety of co-administered paritaprevir plus ritonavir, ombitasvir, and dasabuvir in hepatic impairment

Dasabuvir: A Non-Nucleoside Inhibitor of NS5B for the Treatment of Hepatitis C Virus Infection

In silico studies on therapeutic agents for COVID-19: Drug repurposing approach

Darunavir: A Review in Pediatric HIV-1 Infection

Darunavir: A Review of Its Use in the Management of HIV-1 Infection

Discovering drugs to treat coronavirus disease 2019 (COVID-19)

Therapeutic Options and Critical Care Strategies in COVID-19 Patients; Where Do We Stand in This Battle? Majallahi Danishkadahi Pizishkii Isfahan

Insight derived from molecular docking and molecular dynamics simulations into the binding interactions between HIV-1 protease inhibitors and SARS-CoV-2 3CLpro

Peptide-like and small-molecule inhibitors against Covid-19

Computational View toward the Inhibition of SARS-CoV

Imatinib: A Breakthrough of Targeted Therapy in Cancer

Coronavirus S protein-induced fusion is blocked prior to hemifusion by Abl kinase inhibitors

Virus-Induced Abl and Fyn Kinase Signals Permit Coxsackievirus Entry through Epithelial Tight Junctions

Abl Tyrosine Kinase Regulates Hepatitis C Virus Entry

Productive Replication of Ebola Virus Is Regulated by the c-Abl1 Tyrosine Kinase

Abelson Kinase Inhibitors Are Potent Inhibitors of Severe Acute Respiratory Syndrome Coronavirus and Middle East Respiratory Syndrome Coronavirus Fusion

SARS coronavirus spike protein-induced innate immune response occurs via activation of the NF-κB pathway in human monocyte macrophages in vitro

Imatinib attenuates inflammation and vascular leak in a clinically relevant two-hit model of acute lung injury

Imatinib stimulates prostaglandin E2 and attenuates cytokine release via EP4 receptor activation

Imatinib mesylate induces clinical remission in rheumatoid arthritis

KIT Inhibition by Imatinib in Patients with Severe Refractory Asthma

Long-standing remission of Crohnʼs disease under imatinib therapy in a patient with Crohnʼs disease

Imatinib might constitute a treatment option for lung involvement in COVID-19

European LeukemiaNet recommendations for the management and avoidance of adverse events of treatment in chronic myeloid leukaemia

Principal long-term adverse effects of imatinib in patients with chronic myeloid leukemia in chronic phase

Investigation of N Terminal Domain of SARS CoV 2 Nucleocapsid Protein with Antiviral Compounds Based on

Broad anti-coronaviral activity of FDA approved drugs against SARS-CoV-2 in vitro and SARS-CoV in vivo

Nitazoxanide: A first-in-class broad-spectrum antiviral agent

Nitazoxanide: A New Thiazolide Antiparasitic Agent

Nitazoxanide/azithromycin combination for COVID-19: A suggested new protocol for early management

Therapeutic potential of Nitazoxanide against Newcastle disease virus: A possible modulation of host cytokines

Nitazoxanide, a new drug candidate for the treatment of Middle East respiratory syndrome coronavirus

The Anti-Hepatitis C Agent Nitazoxanide Induces Phosphorylation of Eukaryotic Initiation Factor 2α Via Protein Kinase Activated by Double-Stranded RNA Activation

A screen of the NIH Clinical Collection small molecule library identifies potential anti-coronavirus drugs

Nitazoxanide suppresses IL-6 production in LPSstimulated mouse macrophages and TG-injected mice

A systematic review on use of aminoquinolines for the therapeutic management of COVID-19: Efficacy, safety and clinical trials

The possible mechanisms of action of 4-aminoquinolines (chloroquine/hydroxychloroquine) against Sars-Cov-2 infection (COVID-19): A role for iron homeostasis?

Chloroquine: Modes of action of an undervalued drug

Cardiovascular risks of hydroxychloroquine in treatment and prophylaxis of COVID-19 patients: A scientific statement from the Indian Heart Rhythm Society

Chloroquine and hydroxychloroquine as available weapons to fight COVID-19

Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro

Of chloroquine and COVID-19

Viral infection and iron metabolism

Hepcidin and the Iron-Infection Axis

Iron and infection

Comparison of the Antiviral Activity in vitro of some Non-steroidal Antiinflammatory Drugs

Antihistaminics, local anesthetics, and other amines as antiviral agents

Effect of chloroquine on the growth of animal viruses

In vitro inhibition of severe acute respiratory syndrome coronavirus by chloroquine

A systematic review on the efficacy and safety of chloroquine for the treatment of COVID-19

Chloroquine and hydroxychloroquine in the treatment of COVID-19 with or without diabetes: A systematic search and a narrative review with a special reference to India and other developing countries

Structural and molecular modelling studies reveal a new mechanism of action of chloroquine and hydroxychloroquine against SARS-CoV-2 infection

Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial

Hydroxychloroquine in the management of critically ill patients with COVID-19: the need for an evidence base

Association of Treatment with Hydroxychloroquine or Azithromycin With In-Hospital Mortality in Patients With COVID-19 in New York State

Observational Study of Hydroxychloroquine in Hospitalized Patients with Covid-19

This National clinical trial aims to identify treatments that may be beneficial for people hospitalised with suspected or confirmed COVID-19 2020

Ivermectin: enigmatic multifaceted 'wonder' drug continues to surprise and exceed expectations

Ivermectin is a specific inhibitor of importin α/β-mediated nuclear import able to inhibit replication of HIV-1 and dengue virus

Ivermectin is a potent inhibitor of flavivirus replication specifically targeting NS3 helicase activity: new prospects for an old drug

Repurposing Ivermectin to inhibit the activity of SARS CoV2 helicase: possible implications for COVID 19 therapeutics

Influenza A viruses escape from MxA restriction at the expense of efficient nuclear vRNP import

Nuclear localization of dengue virus (DENV) 1-4 non-structural protein 5; protection against all 4 DENV serotypes by the inhibitor Ivermectin

The broad spectrum antiviral ivermectin targets the host nuclear transport importin α/β1 heterodimer

Nucleocytoplasmic transport of nucleocapsid proteins of enveloped RNA viruses

Severe Acute Respiratory Syndrome Coronavirus ORF6

Antagonizes STAT1 Function by Sequestering Nuclear Import Factors on the Rough Endoplasmic Reticulum/Golgi Membrane

The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro

The importin α/β-specific inhibitor Ivermectin affects HIF-dependent hypoxia response pathways

Antiviral treatment of COVID-19

Hydroxychloroquine and ivermectin: A synergistic combination for COVID-19 chemoprophylaxis and treatment?

Therapeutic potential of ivermectin for COVID

Enhancing immunity in viral infections, with special emphasis on COVID-19: A review

Safety of high-dose ivermectin: a systematic review and meta-analysis

Five-Membered Heterocycles: Indole and Related Systems. Modern Heterocyclic Chemistry

A review on recent developments of indole-containing antiviral agents

Discovery of novel multi-target indole-based derivatives as potent and selective inhibitors of chikungunya virus replication

Medicinal applications of (benz)imidazole-and indole-based macrocycles

Medicinal chemistry of indole derivatives: Current to future therapeutic prospectives

Synthesis and antiviral activity of some novel indole-2-carboxylate derivatives

Superior inhibition of influenza virus hemagglutinin-mediated fusion by indole-substituted spirothiazolidinones

Arbidol combined with LPV/r versus LPV/r alone against Corona Virus Disease 2019: A retrospective cohort study

Arbidol monotherapy is superior to lopinavir/ritonavir in treating COVID-19

The anti-influenza virus drug, arbidol is an efficient inhibitor of SARS-CoV-2 in vitro

Pharmacokinetics of single and multiple oral doses of arbidol in healthy Chinese volunteers

Rizatriptan vs Sumatriptan in the Acute Treatment of Migraine

Ação da melatonina no tecido cartilaginoso

COVID-19: Melatonin as a potential adjuvant treatment

Protective effects of melatonin in mice infected with encephalitis viruses

Melatonin: its possible role in the management of viral infections-a brief review

Network-based drug repurposing for novel coronavirus 2019-nCoV/SARS-CoV-2

Lungs as target of COVID-19 infection: Protective common molecular mechanisms of vitamin D and melatonin as a new potential synergistic treatment

Emetine protects mice from enterovirus infection by inhibiting viral translation

Emetine inhibits Zika and Ebola virus infections through two molecular mechanisms: inhibiting viral replication and decreasing viral entry

High-Throughput Screening and Identification of Potent Broad-Spectrum Inhibitors of Coronaviruses

The Natural Compound Homoharringtonine Presents Broad Antiviral Activity In Vitro and In Vivo

Novel Antiviral Activities of Obatoclax, Emetine, Niclosamide, Brequinar, and Homoharringtonine

Tracing the journey of disulfiram: From an unintended discovery to a treatment option for alcoholism

Supervised Disulfiram as Adjunct to Psychotherapy in Alcoholism Treatment

The Clinical Use of Disulfiram (Antabuse®): A Review

Disulfiram inhibits the in vitro growth of methicillin-resistant staphylococcus aureus

Disulfiram, an alcohol dependence therapy, can inhibit the in vitro growth of Francisella tularensis

Structural Basis for Inactivation of Giardia lamblia Carbamate Kinase by Disulfiram

Disulfiram/copper markedly induced myeloma cell apoptosis through activation of JNK and intrinsic and extrinsic apoptosis pathways

Disulfiram is a direct and potent inhibitor of human O6-methylguanine-DNA methyltransferase (MGMT) in brain tumor cells and mouse brain and markedly increases the alkylating DNA damage

Disulfiram can inhibit MERS and SARS coronavirus papain-like proteases via different modes

Coronaviruses -drug discovery and therapeutic options

Inhibition of Urease by Disulfiram, an FDA-Approved Thiol Reagent Used in Humans

The Microcirculation and Inflammation: Site of Action for Glucocorticoids

The convalescent sera option for containing COVID-19

The possible of immunotherapy for COVID-19: A systematic review

Perspectives on monoclonal antibody therapy as potential therapeutic intervention for Coronavirus disease-19 (COVID-19)

Potential Rapid Diagnostics, Vaccine and Therapeutics for 2019 Novel Coronavirus (2019-nCoV): A Systematic Review

Advances in respiratory virus therapeutics -A meeting report from the 6th isirv Antiviral Group conference

A mouse model for MERS coronavirus-induced acute respiratory distress syndrome

Neutralizing human monoclonal antibodies to severe acute respiratory syndrome coronavirus: target, mechanism of action, and therapeutic potential

Effective treatment of severe COVID-19 patients with tocilizumab

Neutralizing Antibodies against SARS-CoV-2 and Other Human Coronaviruses

Potent binding of 2019 novel coronavirus spike protein by a SARS coronavirus-specific human monoclonal antibody

A human monoclonal antibody blocking SARS-CoV-2 infection

Treatment with Convalescent Plasma for Influenza A (H5N1) Infection

Convalescent Plasma Treatment Reduced Mortality in Patients with Severe Pandemic Influenza A (H1N1) 2009 Virus Infection

Evaluation of Convalescent Plasma for Ebola Virus Disease in Guinea

The Effectiveness of Convalescent Plasma and Hyperimmune Immunoglobulin for the Treatment of Severe Acute Respiratory Infections of Viral Etiology: A Systematic Review and Exploratory Meta-analysis

Feasibility, safety, clinical, and laboratory effects of convalescent plasma therapy for patients with Middle East respiratory syndrome coronavirus infection: a study protocol

Treatment of 5 Critically Ill Patients With COVID-19 With Convalescent Plasma

Convalescent plasma as a potential therapy for COVID-19

Developing Covid-19 Vaccines at Pandemic Speed

A decade after SARS: strategies for controlling emerging coronaviruses

Severe acute respiratory syndrome vaccine development: experiences of vaccination against avian infectious bronchitis coronavirus

SARS coronavirus: a new challenge for prevention and therapy

Coronavirus Pathogenesis and the Emerging Pathogen Severe Acute Respiratory Syndrome Coronavirus

Development of an inactivated vaccine candidate for SARS-CoV-2

Don't rush to deploy COVID-19 vaccines and drugs without sufficient safety guarantees

The authors would like to thank FACEPE (Fundação de Amparo à Ciência e Tecnologia 

None.

All authors researched data for the article, contributed substantially to discussion of the content, wrote the article and reviewed and edited the manuscript before submission.