key: cord-0968467-zpx7nm3r
authors: Chugh, Heerak; Awasthi, Amardeep; Agarwal, Yashi; Gaur, Rajesh K.; Dhawan, Gagan; Chandra, Ramesh
title: A Comprehensive Review on Potential Therapeutics Interventions for COVID-19
date: 2020-11-20
journal: Eur J Pharmacol
DOI: 10.1016/j.ejphar.2020.173741
sha: 43eaf24cda230692c6e61eb5eab7ead85e1c9603
doc_id: 968467
cord_uid: zpx7nm3r

COVID-19 is an infectious respiratory disease caused by SARS-CoV-2, a new beta coronavirus that emerged in Wuhan, China. Being primarily a respiratory disease, it is highly transmissible through both direct and indirect contacts. It displays a range of symptoms in different individuals and thus has been grouped into mild, moderate, and severe diseases. The virus utilizes spike proteins present on its surface to recognize ACE-2 receptors present on the host cells to enter the cell cytoplasm and replicate. The viral invasion of cells induces damage response, pyroptosis, infiltration of immune cells, expression of pro-inflammatory cytokines (cytokine storm), and activation of the adaptive immune system. Depending on viral load and host factors like age and underlying medical conditions, the immune responses mounted against SARS-CoV-2 may cause acute respiratory distress syndrome (ARDS), multiple organ failure, and death. In this review, we specify and justify both viral and host therapeutic targets that can be modulated to relieve the symptoms and treat the disease. Furthermore, we discuss vaccine development in the time of pandemic and the most promising vaccine candidates by far, according to WHO database. Finally, we discuss the conventional re-purposed drugs and potential alternative treatments as adjuvants.

Coronavirus disease 2019 or COVID-19 pandemic has infected 50,266,033 individuals and claimed 1,254,567 lives in 216 countries or territorial regions in approximately half a year (WHO, 2020a). The pathogen responsible for COVID-19 was initially isolated from individuals with severe pneumonia of then-unknown cause in Wuhan city, Hubei Province, China, the epicenter of the outbreak in December 2019 (Lu et al., 2020a) . The pathogen was identified as the seventh coronavirus that could infect humans and was named as SARS-CoV-2 due to its similarities with the sister virus, SARS-CoV (outbreak caused in 2003), (Gorbalenya et al., 2020 and . Since the initial cases in Wuhan were presented from and around the local seafood market or wet market, which is also a hub for live animal trading, an animal to human transmission of the virus was suggested (Singhal, 2020) . Initially, the origin of SARS-CoV-2 has been controversial. While natural evolution from precursor viruses was a possibility, some scientists believed that it was genetically engineered in a laboratory that was working on bat CoV-RaTG13. However, the latter has been rejected since the nucleotide difference between the two viruses is distributed throughout the genome randomly instead of more targeted and logical insertions as would be expected in synthetic constructs, making RatG13 unlikely a direct source for SARS-Cov-2 . On a genomic level, SARS-CoV-2 is more similar to RatG13 (96.2%) and pangolin-CoV (91.02%) than SARS-CoV (70%), indicating both bats, and pangolins could be the reservoir hosts . The SARS-CoV-2 could have been originated from a precursor that underwent natural selection in one of the animal hosts like bats or pangolins under high population density. Alternatively, it might have jumped to humans from the animal hosts and evolved through human to human transmissions.

Finally, a less likely accidental laboratory release of a progenitor virus of SARS-CoV-2 or SARS-CoV-2 itself (Andersen et al., 2020) cannot be ruled out. Another debate that is uprising among the scientific J o u r n a l P r e -p r o o f 8 The use of Personal Protective Equipment and surveillance of local infection and transmission is necessary for these healthcare settings. While social distancing, respiratory etiquette, maintaining selfhygiene, and environmental disinfection remain the WHO recommended preventive measures, an effective therapeutic measure is scarce. Herein, we review potential therapeutic targets and strategies, both conventional and alternative, along with vaccine candidates in clinical trials against COVID-19.

The outbreak of the novel COVID-19 infection has put immense pressure on the research and clinical communities across the world for the development of therapeutics to combat the ever-growing pandemic. However, successful completion of drug development may require several years with no guarantee. Alternatively, the already established drugs can be repurposed to treat the COVID-19

infection. Whether it is the development of new drugs/ vaccines or repurposing of commercial medications, precise information of the potential target(s) is required. These targets can be of two different types; they can be either of SARS-CoV-2 origin or can belong to the human immune system (Sanders et al., 2020) . Sequencing of the viral genome and various computational methods has led (Wu et al., 2020b) to the identification of 18 viral proteins as a potential target for therapeutic intervention.

These proteins can be distributed under the functions they perform 1) RNA synthesis and replication: viable and the manufacturers at possible financial risk (Lurie et al., 2020) . The current situation calls for strong international ties and coordinated efforts for the development of vaccines, policies, funding, manufacturing, and distribution. Given the urgent need for a vaccine to fight an infectious disease like COVID-19, already established platforms are being utilized for the development of vaccination by early 2021 (Le et al., 2020) . According to WHO, currently, there are 180 vaccine candidates out of which 36

candidates are in the clinical trial (Table I) , while 145 are in pre-clinical investigations (WHO 2020c).

Moderna, a Boston based company and researchers at the University of Oxford, published the results of their eagerly anticipated clinical trials, (Jackson et al., 2020) (Phillips et al., 2020) . The Moderna mRNA-1273 is an mRNA-based vaccine that codes for a complete prefusion stabilized spike (S) protein of SARS-CoV-2 encapsulated in a novel lipid nanoparticle (LNP). Moderna trial included 45 healthy adults, 18 to 55 years of age. Individuals received two vaccinations, 28 days apart with dose ranging from 25-200 mg.

The mRNA-1273 vaccine-elicited anti-SARS-CoV-2 immune response in all participants without any safety concern. Importantly, the 100 ug dose was found to induce a high neutralizing response. Unlike mRNA-1273, the oxford candidate vaccine (AZD1222) has been adapted from chimpanzee's adenovirus- J o u r n a l P r e -p r o o f spike-trimer protein of SARS-CoV2 along with a toll-like receptor 9 (TLR9) agonist adjuvant (dynavax.com, 2020) . New viral candidates are being developed in different parts of the world, and an up-to-date brief summary of such candidates that have advanced to clinical trials can be found in Table   1 . 

Undoubtedly, the development and manufacturing of a vaccine are crucial in preventing the COVID-19

pandemic. However, even under extreme pressure of a pandemic and with rigorous efforts being made, the development of a safe and effective vaccine is time-consuming. The repurposing of existing drugs against SARS, MERS, HIV/AIDS, and malaria has proven to be an effective alternate strategy for the treatment of COVID-19 (Li and De Clercq, 2020) . Drug repurposing strategy can potentially shorten the time and as well as reduce the cost compared to develop novel drugs . In this section, we have classified and discussed some frontline re-purposed drugs based on their mode of action against SARS-COV-2.

J o u r n a l P r e -p r o o f 

The endocytic entry of coronavirus involves complexation of transmembrane spike (S) glycoprotein of the virus with angiotensin-converting enzyme 2 (ACE2) and TMPRSS2 (De Savi et al., 2020) . Hence, targeting these interactions and blocking the endolysosomal pathway can lead to a potential treatment for SARS-CoV-2. Here, we describe the re-purposed drugs that can potentially target the fusion of SARS-CoV-2 into the host cells.

For decades, Hydroxychloroquine (HCQ) and Chloroquine (CQ) have been well-known drugs to treat malaria. HCQ is also able to treat rheumatoid arthritis and systemic lupus erythematosus (Savarino et al., 2003) . However, HCQ and CQ have some side effects as well, for instance, headache, dizziness, diarrhea, stomach cramps, and vomiting. In malaria, CQ and HCQ affect heme polymerase process by the accumulation of cytotoxic heme that kills the parasite. Although the exact mechanism is not known, it is believed that these drugs enhance endosomal pH, thereby affecting the fusion of SARS-CoV-2 into host cells (Vincent et al., 2005) . In addition, HCQ and CQ can also diminish the cytokine storm by interfering with the IL-6 pathway. There are over 77 clinical trials that have been registered on HCQ by various companies and institutions. The combination therapy of these two drugs with azithromycin and zinc have also been proposed but led to some severe side effects such as fatal arrhythmia (Gautret et al., 2020) . On 5th June 2020, RECOVERY trial recommended that there are no significant improvements in hospitalized COVID-19 patients after treating with HCQ (recoverytrial.net, 2020a). A randomized study was conducted on 1542 patients, and compared with 3132 patients with standard care, it was observed that there was no substantial difference in the 28-day mortality endpoint (25.7% HCQ vs. 23.5% standard care; p = 0.10). As on 15th

June 2020, FDA revoked the emergency use of hydroxychloroquine and chloroquine to treat patients with COVID-19, considering the emerging cases of side effects associated with these two drugs (fda.gov, Arbidol is a promising antiviral agent currently being used in Russia and China for the treatment of COVID-19 based on its previous studies. It is an indole-based antiviral drug with no significant side effects. It is established in numerous in-vitro and in-vivo studies (Blaising et al., 2014 ) that arbidol has a broad-spectrum activity against the various infectious disease, which makes arbidol a potential drug candidate against SARS-CoV-2. Arbidol targets the interactions of spike glycoprotein (S) of coronavirus and ACE2 and inhibits the membrane fusion of the viral envelope (Kadam and Wilson, 2017) . Currently, five clinical trials have been registered, which involve arbidol. In March 2020, a study conducted in China observed that 69 COVID-19 patients who were given arbidol showed lower mortality rates and higher discharge rates in a median duration of 9 days (Wang et al., 2020b) . The efficacy of arbidol is also being evaluated in combination with Bromhexine Hydrochloride tablets and recombinant human interferon-α 2b (clinicaltrials.gov, 2020i). In June 2020, DCGI, Government of India gave its approval to CSIR-Central Drug Research Institute (CDRI) Lucknow, to commence randomized, placebo, and double-blind phase III clinical trial to authenticate efficacy and safety of arbidol (csir.res.in., 2020). Arbidol hydrochloride is currently in randomized phase IV clinical trials in the USA, wherein 380 COVID-19 patients will be given a dose of 200 mg arbidol orally every 8 hours to evaluate efficacy and safety of this drug (NCT04260594) (clinicaltrial.gov, 2020j). The requirement of a large number of doses to achieve peak plasma concentration and therapeutic efficacy is one of the major drawbacks of the drug.

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Camostat is a serine protease inhibitor manufactured by Ono Pharmaceutical Co. Ltd in 1977. The current form of the drug is also valuable in the treatment of cancer (Okuno et al., 2002) and some viral infections (Hsieh and Hsu., 2007) . Nafamostat mesylate, another serine protease inhibitor, is commonly used as an anticoagulant (Al-Horani and Desai, 2014), and also as an antiviral and anticancer drug (Chen et al., 2019) . CoV by inhibiting the TMPRSS2 in HeLa cell lines (Kawase et al., 2012) . Recently, a study reported that camostat could block SARS-CoV-2 in a mouse model at a concentration that is tolerated in humans (clinicaltrials.gov, 2020k). These studies make this drug a suitable candidate to treat patients infected with SARS-CoV-2. Currently, there are six clinical trials registered to substantiate the efficacy of Camostat for COVID-19 in Germany, Netherland, Denmark, and Japan (clinicaltrials.gov, 2020l).

Baricitinib, a Janus kinase (JAK) inhibitor, is currently sold for the treatment of rheumatoid arthritis (RA) (fda.gov, 2020b). It selectively and reversibly binds JAK receptors and is successful in inhibiting JAK1/2 subtype. It effectively disrupts the cytokine-mediated signal transduction through JAKs and discourages the development of inflammatory response (Genovese et al., 2016) . Baricitinib also prevents the fusion of the virus into the host cells by inhibiting the AAK1 receptor, a member of the kinase family, and one of the regulators of endocytosis (Lu et al., 2020b) . Thus, Baricitinib may be a potential option to treat Covid-19. It has been reported that 2 to 4 mg of Baricitinib is suitable for inhibiting the AAK1 receptor and may be useful in the treatment of COVID patients (Favalli et al., 2020a) . Pharmacokinetic studies suggest that there is 79% oral bioavailability in humans, and approximately 1hr is sufficient to reach peak plasma concentration. Some of the side effects associated with this drug are malignancy and thrombosis (Kuriya et al., 2017) . There are sixteen clinical trials registered by various organizations to determine the efficacy of this drug in different combinations such as hydroxychloroquine, ritonavir (clinicaltrials.gov, 2020m), and remdesivir (nih.gov, 2020) against COVID-19.

Upon the fusion of viral and host cell membranes, SARS-CoV-2 injects the positive-sense single-stranded RNA (+SSRNA) into the cytoplasm. The RNA binds to the ribosomes for translation of polyproteins, which in turn give rise to structural and non-structural proteins. Among these, 3-chymotrypsin-like protease (3CLpro) and papain-like protease (PLpro) play an essential role in the virus' life cycle since they cleave the polyproteins (PP1A and PP1AB) into functional viral proteins, making them a suitable therapeutic target . Computer-aided drug design has been employed to annotate the potential inhibitors for proteases (Kumar et al., 2020b) . (Igbinosa et al., 2020) . On the other hand, NNIs bind the polymerase at its allosteric site, modifying the conformation and thus the polymerase activity is halted with low toxicity and side effects. Nucleotide analogs have been used as successful antiviral agents as they can effectively block RdRp activity and inhibit viral replication. In this section, we have discussed the potential use of RdRp inhibitors, such as remdesivir and favipiravir.

Remdesivir (RDV), previously known as GS-5734, is one of the frontline drug candidates for SARS-CoV-2.

Remdesivir is an analog of 1'-cyano-substituted adenosine triphosphate nucleoside and is effective against a broad spectrum for viral infections. Moreover, it is a phosphoramidate prodrug, which gets Some of the side effects associated with this drug are low blood pressure, inflammation in the liver, and sweating (ema.europa.eu, 2020). In April 2020, remdesivir was considered a potential candidate drug and included in clinical trials by SOLIDARITY and European Discovery trial to establish efficacy against COVID-19, (Karki, 2020) (inserm.fr., 2020). Wang et al. reported promising in-vitro studies of remdesivir on human cell lines against SARS-CoV-2 infection40 (Wang et al., 2020a) . In January 2020, the first US COVID-19 infected patient (35-year-old man) recovered after intravenous administration of remdesivir without any adverse side effects (Holshue et al., 2020) . According to the recent clinical trials, the current dose for the infected patient is 200 mg on day one, followed by 100 mg daily intravenously administration of remdesivir for 5 to 10 days (clinicaltrials.gov, 2020n). Currently, 19 clinical trials are underway to evaluate the efficacy of remdesivir. As of 1st June 2020, Gilead Sciences announced Phase III trial results of remdesivir in patients with moderate to severe COVID-19. It is reported that moderate cases of COVID-19 patients show 65% of clinical improvement on a 5-day dose of remdesivir than patients who had standard care of 11 days (P = .077) (gilead.com, 2020) . Also, in another published report, 64% and 54% of severe COVID-19 patients who were treated with five and a 10-day course of remdesivir, respectively, have shown clinical improvement by day 14 compared to those who received standard care (Goldman et al., 2020) . Though the results are not statistically significant, remdesivir has emerged as a leading drug for the SARS-CoV-2. The US, India, Singapore, and Japan approved remdesivir for emergency treatment of hospitalized patients with severe Covid-19. However, On 15 th October 2020, WHO concluded in their solidarity trials that Remdesivir have little or no effect on hospitalized COVID

Patients (Pan et al., 2020) .

The administration of the Remdesivir in the patients has been a major problem since the drug gets largely metabolized by the body in the oral delivery and does not affect the viral infection site effectively. Recently, to enhance the absorption rate and efficacy of the Remdesivir, a research group in University of Texas has developed inhaled form of Remdesivir (dry powder) using thin film freezing (TFF) (Sahakijpijarn et al., 2020) . It was observed in the in-vivo studies that only 10mg/kg dose of dry powder form of Remdesivir achieved necessary EC50 value to inhibit the viral infection. On 8th July 2020, Gilead

Sciences has also initiated randomized, placebo-controlled Phase 1a clinical trials of inhaled solution of

Remdesivir to evaluate safety, pharmacokinetics and tolerability of the drug in the non-hospitalized patients (Gilead.com, 2020).

Favipiravir (FPV), sold under the brand name Aviga® is an antiviral agent developed for the treatment of influenza ABC viruses in Japan (Du, and Chen, 2020) . Favipiravir is an analog of pyrazine carboxamide.

Once administered, its rapid phosphorylation generates pharmacologically active form favipiravir-RTP (ribofuranosyl-5′-triphosphate). The FPV-RTP serves as a substrate for RdRp, which results in the termination of the nascent RNA chain and inhibition of virus replication (Furuta et al., 2005) . It has shown efficacy against a broad spectrum of viruses such as Ebola, arenavirus, H1N1, filovirus, and bunyaviruses, (Delang et al., 2018) (Sissoko et al., 2016) . 

The most striking clinical feature of COVID-19 is the presence of elevated pro-inflammatory cytokines in the sera of COVID-19 patients. Severe cases display even higher levels of cytokines giving rise to "cytokine storm," which further increases disease severity leading to ARDS, multiple organ failure, and death. Therefore, targeting cytokine production could be a potential therapeutic option for severely infected patients with COVID-19 (Coperchini et al., 2020) . The elevated level of IL-6 has been linked to the severity of the disease and as a prognostic marker for the negative outcome. Tocilizumab and sarilumab are some of the repurposed drugs, which can inhibit the IL-6+ receptor and downstream signaling cascade.

Tocilizumab is an immunosuppressant drug that is sold under the brand name Actemra® and was developed by Hoffmann-La Roche and Chugai (Venkiteshwaran, 2009 ). It is a recombinant humanized monoclonal antibody of IgG1 subclass, which targets IL-6R, both membrane-bound and soluble forms.

Binding of tocilizumab to IL-6R prevents its dimerization and interaction with GP130 transmembrane receptor leading to inhibition of downstream JAK-STAT or MAPK signaling pathways and attenuation of inflammatory responses. Tocilizumab is approved in the EU to treat rheumatoid arthritis (Oldfield et al.,

follows both linear and nonlinear pharmacokinetics with a half-life of 11hr for 4kmg/kg dose. In China, out of 21 COVID-19 patients who were treated with tocilizumab (400 mg per day), 20 recovered within two weeks without any side effects associated with tocilizumab (Xu et al., 2020b) . A recent study has reported promising results of intravenous tocilizumab in severely infected patients (Guaraldi et al., 2020) . Treatment with tocilizumab reduced excessive use of ventilation and reduced the death count with an adjusted hazard ratio of 0·61, 95% CI 0·40-0·92; P=0·020. In order to evaluate the efficacy and safety of tocilizumab and remdesivir, Genentech has initiated a Phase III, randomized, double-blind, multicenter study (REMDACTA) (gene.com, 2020).

Corticosteroids are broad-spectrum drugs, known to attenuate inflammation. They are used for the treatment of autoimmune and inflammatory diseases, including inflammatory bowel disease, asthma, rheumatoid arthritis, and allergy (Schäcke et al., 2002) . Their use is controversial due to the side effects associated with their use, such as Cushing's syndrome, diabetes, hypertension, and skin atrophy, which (Stockman et al., 2006) . Nevertheless, reduced mortality rates and lesser hospital stays of 401 patients infected with SARS (Chen et al., 2006) were reported. A recent study involving 10 COVID-19 patients, administered with a dose of 190mg/day of corticosteroid and a dose of 20g/day of immunoglobulin, showed improved results without any adverse side effects . However, in a separate study of 416 COVID-19 patients, it was observed that improved results by administering corticosteroid and gamma globulin are associated with low lymphocyte counts in patients (Shang et al., 2020b) .

Corticosteroids are currently administered in the systematic and inhaled form. Administration of inhaled corticosteroids (ICS) is still in the shadow of uncertainty, since a study of OpenSAFELY group suggested that ICS in 966,461 patients with asthma and chronic disease did not show good results (Schultze et al., 2020) . Nonetheless, ICS has been proven to be effective in reducing 50% ARDS in high risk patients (Ortiz-Diaz et al., 2011) . In-vitro studies in infected epithelial cells also support role of ICS in inhibiting replication step of coronavirus (Yamaya et al., 2020) . Inhaled Ciclesonide has also been reported effective in blocking SARS-CoV-2 replication in vitro studies with EC90 0.55 μM (Matsuyama et al., 2020) . Inhaled Ciclesonide has also successfully treated three mild cases of covid patients in Hong

Kong in low dose of drug, however efficacy of this drug cannot be established in such small sample (Iwabuchi et al., 2020) .

Dexamethasone, cheaply available corticosteroids, was approved for the treatment of inflammatory diseases (Fischer and Ganellin, 2010) . On 16th June 2020, researchers from Oxford University announced a major breakthrough in a clinical trial of severely ill COVID-19 patients. It was observed that the administration of dexamethasone significantly reduced the deaths of patients (ox.ac.uk, 2020). 

Convalescent plasma therapy (CPT) is a passive immunization initially used against Diptheria in 1890 (Behring, 1890) . Convalescent Plasma is obtained from recovered patients, who developed humoral immunity. Convalescent Plasma consists of neutralizing antibodies (Nabs) as a critical component that reduces viremia. Additional components include non-neutralizing antibodies (Non-Nabs), antithrombotic factors, immunoglobulin, and anti-inflammatory cytokine, which may be immunomodulatory in effect (Pandey et al., 2020) . Convalescent plasma therapy has been effective in treating SARS-1 and MERS patients and has shown immediate but temporary immunity in COVID-19 patients . To test the effectiveness of CP, a pilot study involving ten critically ill COVID-19 patients, median aged 52.5 years, was conducted. It was established that each patient developed high NAbs titre with significant viral shedding and improved clinical symptoms (fever, trouble breathing, cough, etc.) within three days of 200 ml CP infusion. Alongside elevated oxyhaemoglobin, improvement in lung lesions and lymphocyte numbers, and decreased inflammation was observed (Bloch et al., 2020) . In a second study, five critically ill COVID-19 patients, aged 18-60 were subjected to CP transfusion with a nCoV-2019 specific antibody (IgG) and neutralizing antibody. Within a few days of CP transfusion, a decline in the SARS CoV-2 RNA load and improved clinical conditions were observed . An open-label clinical study demonstrated that 80% of CP recipients developed appreciably high antibody titer three days post-infusion of 400 ml CP dose, irrespective of donor antibody titer. Moreover, repeat administration of CP dose in one patient was well tolerated, and CPT did not result in any adverse effects (Madariaga et al., 2020) .

In the first randomized controlled clinical trial in 103 patients, 52 were administered with CP along with standard care, while 51 received standard care only. The results indicate that the use of CP failed to accomplish clinical improvements in critically ill patients. However, clinical symptoms improved in severely ill patients within 28 days of symptom onset. The study suggests that viral elimination and inflammation reduction might occur before clinical benefits. Therefore, the right phase and right time for CP injection is a must for its replete therapeutic utilization (Zeng et al., 2020) . CPT may have a synergistic effect in treating COVID-19 in combination with antiviral drugs such as remdesivir (Casadevall and Scharff, 1995) .

J o u r n a l P r e -p r o o f are required for ensuring the reliability of CPT against novel coronavirus. Donor criteria, optimum dose, and serological assay (to determine SARS CoV-2 in serum) are still needed to be precisely ascertained. 

The lack of an effective therapeutic strategy against COVID-19 has prompted scientists to investigate the use of alternative medicines in the fight against coronavirus infection. China initiated this approach, wherein it dexterously utilized its concept of Traditional Chinese Medicine (TCM). An in-silico study yielded 13 molecular compounds found in 230 medicinal herbs used in TCM, to target SARS-CoV-2 associated factors such as the spike protein, 3CLpro, and PLpro. By screening for herbs that contain more than one of these 13 compounds, and have been used as a part of TCM to treat respiratory viral infections, 26 medicinal herbs were identified against COVID-19 infection (Zhang et al., 2020c) . shutdown to contain the virus, which could be an effective approach to combat the virus.

The current coronavirus pandemic is unprecedented and requires extraordinary efforts from the scientific community across the globe. Incidentally, SARS, and MERS outbreaks have provided important insights to understand SARS-CoV-2 pathogenesis and execute effective therapeutic strategies to combat COVID-19. However, rigorous research and human clinical trials of repurposed drugs and future vaccines are required to authenticate the efficacy and safety of proposed treatment options. Repurposed drugs such as Remdesivir, Faipiravir, and Dexamethasone, reportedly decreased fatality rates and improved recovery rates in several human clinical trials. Nonetheless, the development and distribution of a safe and effective vaccine is a crucial preventive strategy to limit the COVID-19 pandemic. In the meantime, preventive measures imposed by governments and public corporations are proving to be successful in containing the spread of SARS-CoV-2.

J o u r n a l P r e -p r o o f wherein it replicates and assembles more virus particles, which then invade neighboring cells. Host immunity surveillance recognize the viral particles and mount an immune response that may be overdriven to cause ARDS, multi-system organ failure and death (Created with BioRender.com). 

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Favipiravir: pharmacokinetics and concerns about clinical trials for 2019-nCoV infection

Effectiveness of convalescent plasma therapy in severe COVID-19 patients

Biopharmaceuticals Announce Research Collaboration to Evaluate Coronavirus (COVID-19) Vaccine Candidate with CpG 1018 Adjuvant (2020)

(accessed on 15th (fda.gov, 2020c) US food & drug administration development & approval process (CBER) investigational COVID-19 convalescent plasma -emergency INDs

Analogue-based drug discovery

Mechanism of action of T-705 against influenza virus

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

The New Pandemic Covid-19: Treatment Options and Developments

Genentech Initiates Phase III Clinical Trial of Actemra Plus Remdesivir in Hospitalized Patients with Severe COVID-19 Pneumonia

Baricitinib in patients with refractory rheumatoid arthritis

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Harnessing innate immunity to eliminate SARS-CoV-2 and ameliorate COVID-19 disease

Severe acute respiratory syndrome-related coronavirus: The species and its viruses-a statement of the Coronavirus Study Group

Tocilizumab in patients with severe COVID-19: a retrospective cohort study

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COVID-19: faecal-oral transmission

JAK2 Mutations and JAK Inhibitors in the Management of

A multibasic cleavage site in the spike protein of SARS-CoV-2 is essential for infection of human lung cells

SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor

Cellular entry of the SARS coronavirus

First case of 2019 novel coronavirus in the United States

Strategies of development of antiviral agents directed against influenza virus replication

Evaluation of metal-conjugated compounds as inhibitors of 3CL protease of SARS-CoV

Use of remdesivir for pregnant patients with severe novel coronavirus disease 2019

Therapeutic potential of ciclesonide inahalation for COVID-19 pneumonia: Report of three cases

An mRNA vaccine against SARS-CoV-2 preliminary report

Clinical characteristics of 51 patients discharged from hospital with COVID-19 in

Structural basis of influenza virus fusion inhibition by the antiviral drug Arbidol

Identification of novel compounds against three targets of SARS CoV-2 coronavirus by combined virtual screening and supervised machine learning

Solidarity Trial": A Feeling of Trust Towards COVID-19 Treatments

Simultaneous treatment of human bronchial epithelial cells with serine and cysteine protease inhibitors prevents severe acute respiratory syndrome coronavirus entry

Combination therapy with lopinavir/ritonavir, ribavirin and interferon-α for middle east respiratory syndrome

Antitussive noscapine and antiviral drug conjugates as arsenal against COVID-19: a comprehensive chemoinformatics analysis

Understanding the binding affinity of noscapines with protease of SARS-CoV-2 for COVID-19 using MD simulations at different temperatures

Baricitinib in rheumatoid arthritis: evidence-to-date and clinical potential

The COVID-19 vaccine development landscape

Functional assessment of cell entry and receptor usage for SARS-CoV-2 and other lineage B betacoronaviruses

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

Single-cell landscape of bronchoalveolar immune cells in patients with COVID-19

Chronic obstructive pulmonary disease is associated with severe coronavirus disease 2019 (COVID-19)

No credible evidence supporting claims of the laboratory engineering of SARS-CoV-2

Outbreak of pneumonia of unknown etiology in Wuhan, China: The mystery and the miracle

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

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Clinical predictors of donor antibody titer and correlation with recipient antibody response in a COVID-19 convalescent plasma clinical trial

The inhaled steroid ciclesonide blocks SARS-CoV-2 RNA replication by targeting viral replicationtranscription complex in culture cells

Pathological inflammation in patients with COVID-19: a key role for monocytes and macrophages

Qingfei Paidu Decoction is an effective prescription for the treatment of mild common pneumonia

Virus against virus: a potential treatment for 2019-nCov (SARS-CoV-2) and other RNA viruses

NIH clinical trial testing antiviral remdesivir plus anti-inflammatory drug baricitinib for COVID-19 begins

No clinical benefit from use of lopinavir-ritonavir in hospitalized COVID-19 patients studied in Recovery

Retinoids in liver fibrosis and cancer

Preadmission use of inhaled corticosteroids is associated with a reduced risk of direct acute lung injury/acute respiratory distress syndrome

A SARS-CoV-2-Human Protein-Protein Interaction Map Reveals Drug Targets and Potential Drug-Repurposing

Potential therapeutic targets for combating SARS-CoV-2: Drug repurposing, clinical trials and recent advancements

Indian traditional ayurvedic system of medicine and nutritional supplementation

PFIZER AND BIONTECH ANNOUNCE VACCINE CANDIDATE AGAINST COVID-19 ACHIEVED SUCCESS IN FIRST INTERIM ANALYSIS FROM PHASE 3 STUDY

Rifampicin and clarithromycin (extended release) versus rifampicin and streptomycin for limited Buruli ulcer lesions: a randomised, open-label, non-inferiority phase 3 trial

Immune responses in COVID-19 and potential vaccines: Lessons learned from SARS and MERS epidemic. Asian Pac

Evaluation of Blood Levels of

RDIF and ChemRar announce the Russian Ministry ofHealth has included Avifavir in the list of nationally recommended drugs for the treatment of COVID-19

Remdesivir: A Review of Its Discovery and Development Leading to Emergency Use Authorization for Treatment of COVID-19

Rigel launches Phase II trial to access fostamatinib for Covid-19 patients

The epidemiology and pathogenesis of coronavirus disease (COVID-19) outbreak

Development of Remdesivir as a Dry Powder for Inhalation by Thin Film Freezing

Pharmacologic treatments for coronavirus disease 2019 (COVID-19): a review

Effects of chloroquine on viral infections: an old drug against today's diseases

Current pharmacological treatments for COVID-19: What's next?

Mechanisms involved in the side effects of glucocorticoids

Inhaled corticosteroid use and risk COVID-19 related death among 966,461 patients with COPD or asthma: an OpenSAFELY analysis

Cell entry mechanisms of SARS-CoV-2

The treatment and outcomes of patients with COVID-19 in Hubei, China: a multi-centered, retrospective, observational study

Computational Guided Drug Repurposing for Targeting 2'-O-Ribose Methyltransferase of SARS-CoV-2

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

Treatment of 5 critically ill patients with COVID-19 with convalescent plasma

A review of coronavirus disease-2019 (COVID-19)

Correction: experimental treatment with favipiravir for Ebola virus disease (the JIKI Trial): a historically controlled

Immunogenicity of a DNA vaccine candidate for COVID-19

SARS: systematic review of treatment effects

HMGB1: A Possible Crucial Therapeutic Target for COVID-19?

On the origin and continuing evolution of SARS-CoV-2

The hallmarks of COVID-19 disease

The Best Global Responses to COVID-19 Pandemic

Breadth of concomitant immune responses prior to patient recovery: a case report of non-severe COVID-19

Public health approach of Ayurveda and Yoga for COVID-19 prophylaxis

ChAdOx1 nCoV-19 vaccination prevents SARS-CoV-2 pneumonia in rhesus macaques

Chloroquine is a potent inhibitor of SARS coronavirus infection and spread

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

Clinical features of 69 cases with coronavirus disease

World Health Organization. (WHO, 2020c) World Health Organization, 2020. DRAFT landscape of COVID-19 candidate vaccines. World. (WHO, 2020d) World Health Organization, 2020. Corticosteroids for COVID-19

Airborne transmission of severe acute respiratory syndrome coronavirus-2 to healthcare workers: a narrative review

SARS-CoV-2 is an appropriate name for the new coronavirus

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

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

Effective treatment of severe COVID-19 patients with tocilizumab

Inhibitory effects of glycopyrronium, formoterol, and budesonide on coronavirus HCoV-229E replication and cytokine production by primary cultures of human nasal and tracheal epithelial cells

Shi Gan Decoction against Coronavirus Disease 2019 (COVID-19): in silico and experimental study

Angiotensinconverting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: molecular mechanisms and potential therapeutic target

In silico screening of Chinese herbal medicines with the potential to directly inhibit 2019 novel coronavirus

Short-Term Moderate-Dose Corticosteroid Plus Immunoglobulin Effectively Reverses

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Immunogenicity and safety of a recombinant adenovirus type-5-vectored COVID-19 vaccine in healthy adults aged 18 years or older: a randomised, double-blind