key: cord-0892891-gblk2z2m
authors: Tuli, Hardeep Singh; Sood, Shivani; Kaur, Jagjit; Kumar, Pawan; Seth, Prachi; Punia, Sandeep; Yadav, Priya; Sharma, Anil Kumar; Aggarwal, Diwakar; Sak, Katrin
title: Mechanistic insight into anti-COVID-19 drugs: recent trends and advancements
date: 2021-02-02
journal: 3 Biotech
DOI: 10.1007/s13205-021-02644-8
sha: bd4211bef85997651707c8544bf3a3a349f63b2d
doc_id: 892891
cord_uid: gblk2z2m

The Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2) has been established now to be a deadly disease afflicting the whole world with worst consequences on healthcare, economy and day-to-day life activities. Being a communicable disease, which is highly pathogenic in humans, causing cough, throat infection, breathing problems, high fever, muscle pain, and may lead to death in some cases especially those having other comorbid conditions such as heart or kidney problems, and diabetes. Finding an appropriate drug and vaccine candidate against coronavirus disease (COVID-19) remains an ultimate and immediate goal for the global scientific community. Based on previous studies in the literature on SARS-CoV infection, there are a number of drugs that may inhibit the replication of SARS-CoV-2 and its infection. Such drugs comprise of inhibitors of Angiotensin-Converting Enzyme 2 (ACE2), transmembrane Serine Protease 2 (TMPRSS2), nonstructural protein 3C-like protease, nonstructural RNA-dependent RNA polymerase (RdRp) and many more. The antiviral drugs such as chloroquine and hydroxychloroquine, lopinavir and ritonavir as inhibitors for HIV protease, nucleotide analogue remdesivir, and broad-spectrum antiviral drugs are available to treat the SARS-CoV-2-infected patients. Therefore, this review article is planned to gain insight into the mechanism for blocking the entry of SARS-CoV-2, its validation, other inhibition mechanisms, and development of therapeutic drugs and vaccines against SARS-CoV-2.

The year 2020 witnessed an outbreak of devastating and pandemic coronavirus disease, COVID-19 which is caused by SARS-CoV-2. The very first case of mortality due to COVID-19 was reported in late December 2019 in the Wuhan city of China (Saxena 2020; Singh and Florez 2020) . Coronavirus has the largest single-stranded positive RNA genome which is packed in the enveloped nucleocapsid protein. It is spherical or pleomorphic in structure with spike-or crown-like projections of glycoproteins with 80-120 nm in diameter on its surface, 6-10 open-reading frames, and 26.2-31.7 kb in size (Yang et al. 2006; Guo et al. 2008; Prajapat et al. 2020; Sood et al. 2020) . Till now, there are seven important strains of human coronavirus (Chang et al. 2016) , whose conserved genes (McBride et al. 2014 ) and structural components (Hilgenfeld 2014) have been depicted in Fig. 1 . The main hypothesized reservoir of SARS-CoV-2 are considered to be bats which transmit the virus to human beings with symptoms such as common cold, respiratory tract infections, cough, fever bronchiolitis and many more (Saif 2004) . During the emergence of Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) in Guangdong province of China in 2003 (http://www.who.int/csr/sars/count ry/table 2004_04_21/en/) and the Middle East respiratory syndrome (MERS-CoV) in the year 2012 in Saudi Arabia, they were declared as emerging viruses because of being adaptive to the changing environments. However, the COVID-19 virus was declared as public emergency on 30 January 2020 by World Health Organization (WHO) because this virus mutated rapidly and its recombination frequency was very high, which further gave rise to newer strains with new virulence characteristics. Therefore, to protect the world, special precautions of social distancing, wearing of masks, sanitization of containment zones, quarantine and lockdowns were adopted by the respective Governments and people (Gennaro et al. 2020; Upadhyay et al. 2020) . The onset of SARS-CoV-19 in Wuhan and the status of infected people worldwide have been shown in Fig. 2 . The increase in the number of patients in coronavirus with symptomatic and asymptomatic conditions and lack of a proper vaccine or drug available for the treatment of patients, have led to an increase in death rate. Therefore, immediate approaches are required to study and design novel antiviral drugs to combat with COVID-19 (Abdul-Rahman et al. 2020; Down et al. 2020; Jin et al. 2020; Bhatia et al. 2020) . To achieve this, various pharmaceutical companies, researchers, drug discovery labs and organizations have explored the identification and evaluation of the target and along with the underlying mechanism (Alexander et al. 2020a, b; Jeon et al. 2020) . Across the world, various therapies, treatments, and clinical trials of vaccines are being carried out by various firms including Moderna and NIAID, BioNTech and Pfizer, Inovio Pharmaceuticals, University of Oxford, AstraZeneca, CanSino Biologics, Wuhan Institute of Biological Products, Beijing Institute of Biological Products, Sinopharm, Sinovac, Institute of Medical Biology and Chinese Academy of Medical Sciences and Novavax. Mullard 2020) . In this article herein, we review the potential drug targets and the putative mechanisms thereof against SARS-CoV-2. Moreover, the review also includes the RNA synthesis inhibitors, antiviral therapies, inhibition of viral endocytosis and ACE2 receptors, antibiotics, inhibition of inflammatory mechanisms mediated by different cytokines and phagocytosis mechanism as well.

Since the beginning of year 2020, COVID-19 has created havoc in the world. It is of paramount importance to develop a vaccine against this virus which is a time-consuming process and need clinical trials (Jiang et al. 2020) . In 2020, Chang et al. recommended drugs which have been used against viral infections which were already approved by US Food and Drug Administration (FDA). Various investigations have been carried out for the treatment of COVID-19 with antiviral compounds which have been proven to inhibit the COVID-19 infection. The proposed drugs which are reported to work against the virus infection with their molecular formula and mechanism of action, have been tabulated in Table 1 . The innate immune system of humans plays an important role in defense against SARS-CoV-19 replication. With the help of interferons, the immune response and the binding of virus to the Angiotensin-Converting Enzyme 2 (ACE2) increase (Omrani et al. 2014) . Coronavirus can be blocked by inhibiting the virus self-assembly through structural proteins, virus association with human cells, inhibiting the replication process of virus by blocking several enzymes and the viral transcription factors (Saikatendu et al. 2005 ). There were three main criteria and strategies based on antiviral compounds which were adopted by scientists and researchers to treat COVID-19 (Huang et al. 2019 ). The first input was to use the drugs associated with cyclophilin inhibitors, interferons and ribavirin which are associated with pneumonia-like symptoms, hence approved for the virus treatment. The major disadvantage of these drugs is that they are broad spectrum and killing the virus in a targeted manner still requires a more in-depth research. The second input was to use the existing literature, molecular databases and to find the new molecules with therapeutic potential which are useful and effective against COVID-19 or coronavirus. The anti-HIV drugs such as ritonavir and lopinavir were discovered as potential therapeutics with high-throughput techniques which further help in the effective functioning of the new molecules (Chen et al. 2014; Mummed 2020) . The last input was based on the coronavirus genetic and pathological features. The 3-D structures of drugs used for the treatment of the Coronavirus-19 have been shown in Fig. 3 which are retrieved from PubChem database . It was supposed that development of drugs through this method will be more efficient and powerful against the virus. But the method was found to be time consuming which could take even more than 10 years to develop the drug after passing all phases of the clinical trials (Omrani et al. 2014; Mummed 2020) . 1 3

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The new therapies for treating the coronavirus are known to act by inhibiting the viral targets and by controlling the infection caused by nucleotide analogues (Raj et al. 2020; Chandel et al. 2020a ). The surface glycoproteins of viruses (Influenza, Ebola, SARS, and MERS) require proteolytic cleavage by a host cell protease. The coronavirus-2 enters the host cells by ligating the spike proteins of the outer membrane of virus with ACE2 receptor as host cell which is further primed by Transmembrane serine protease 2 (TMPRSS2 protease). The replication of the virus and assembly can be blocked by antiviral drugs which target protease 3-chymotrypsin-like cysteine protease (3Clpro) and RNA-dependent RNA polymerase (RdRp) (Bertram et al. 2012; Zhou et al. 2015; Yamaya et al. 2015) .

Endocytosis is a fundamental cellular process through which extracellular material is brought into the cell interior. Classically, it occurs via the regulation of two different modules-pinocytosis (cell drinking) and phagocytosis (cell eating) depending upon the type of molecules approaching towards the cell surface. The foreign molecules (viruses, bacteria, etc.) use endocytosis process to enter inside the cell. Nowadays, it is the utmost need of biologists and researchers to understand the endocytosis mechanism to stop the pathogen particles to enter inside the cell. However, it is not clear until date how this process is regulated at the molecular level. Classically, pinocytosis involves the uptake of liquid particles while phagocytosis, an actin-dependent course involves the internalization of viruses or bacterial particles to the cell (Dutta and Donaldson 2012) . In addition, pinocytosis can be sub-categorized into clathrin-mediated endocytosis (CME) and clathrincoated independent endocytosis (CIE). Cell biologists are now trying to block the entry of SARS-CoV-2 inside the cell via inhibiting the endocytosis process, a novel therapeutic strategy to make the vaccine for curing Covid-19 patients. Endocytosis inhibitors could be chemically and genetically originated consisting of selective pharmacologic agents, molecular agents (inhibitors of selective cell-surface proteins and ribonucleic acid). In the current scenario, therapeutic targets are being tried to design specifically to block the attachment of SARS-CoV-2 with cell-surface protein and endocytosis process (Fig. 4) . The proposed drugs for Covid-19 such as Nafamostat and Camostat block the fusion of SARS-CoV-2 to cell-surface protein (TMPRSS2). Chloroquinone blocks the ACE2 protein-SARS-CoV-2 fusion. Similarly, Xu et al. 2020a, b; Scott 2017 . Clinicaltrial.gov (2020a the other drug Imatinib inhibits the endocytosis process. Baricitinib drug also inhibits the clathrin-mediated endocytosis by blocking the numb-associated kinase (NAK) particularly AAK1 (Stebbing et al. 2020) . As per our best knowledge, chemically and genetically designed inhibitors have been utilized in the preparation of therapeutic targets against SARS-CoV-2 virus, listed in 

ACE2 is mainly present in lungs, kidney, testis, and heart (Donoghue et al. 2009; Ferrario and Varagic 2010; Ohtsuki et al. 2010) and was first discovered in 2000 by Donoghue et al. (2009) . It is expressed in non-keratinized squamous epithelium basal layer of nasopharynx, oral and nasal mucosa basal epidermal skin layer with the strongest expression in type II epithelial cells . However, ACE2 is not expressed in glomerular endothelial and mesangial cells whereas it is slightly expressed in glomerular tubules. Further B cells, T cells, bone marrow, macrophages, thymus, spleen, Kupffer cells, lymph nodes, and hepatocytes do not depict the presence of ACE2 (Hamming et al. 2004; Santos et al. 2018) . ACE2 activity of tissues is higher as compared to its plasma activity (Haber et al. 2014) . ACE inhibitors do not inhibit the activity of ACE2 (Donoghue et al. 2009 ). ACE2 possesses 400 times higher efficiency for angiotensin II (Ang II) than angiotensin I (Ang I) (Vickers et al. 2002) with difference in its activity depending on the sex and age of individuals (Xudong et al. 2006; Soro-Paavonen et al. 2012 ).

One of the worst symptoms of COVID-19 is acute respiratory distress syndrome (ARDS) which causes increased pulmonary edema and pulmonary vascular permeability. The novel coronavirus for invades the human alveolar epithelial cells through ACE2 (Yang and Shen 2020). ACE2 exhibits a protective role in case of ARDS Xu et al. 2020a, b) . When COVID-19 binds to ACE2 receptor it activates the transmembrane serine protease 2 (TMPRSS2), the envelope of the virus fuses with the membrane and thus invades the cells (Fig. 5) (Heurich et al. 2014; Hoffmann et al. 2020 ). ACE2 generates Ang (1-9) by the cleavage of leucine from Ang I and Ang (1-7) by the cleavage of phenylalanine from Ang II (Rossi et al. 2020) . The detrimental effects such as fibrosis, inflammation, and increased vascular permeability, caused by Ang II are counteracted by Ang (1-7). Therefore, ARDS is improved by angiotensin-receptor blockers (ARBs) or ACEIs and Ang (1-7) Wösten-van Asperen et al. 2011; Imai et al. 2005) . The COVID-19 entry to the lung cells could be prevented by TMPRSS2 inhibitors such as nafamostat mesylate (Yamamoto et al. 2016 ) and comstat (Hoffmann et al. 2020) or neutralizing antibodies present in SARS convalescent sera.

Since ACE2 was spotted as the receptor for COVID-19, there were two scientifically unsupported articles which contended that ARB-and ACEI-supplemented treatment for Fig. 4 Schematic representations of viral endocytosis inhibition as promising drug target to block COVID-19 entry. It has been observed that COVID therapeutics inhibit promisingly endosome and lysosome formation, and consequently, it leads to the inhibition of viral replication COVID-19, was harmful for the patients. This caused distress amongst the public and health officials as more patients began to question the treatment given to them. It was also documented in the Lancet Respiratory Medicine journal, that the cardiac (diabetes and/or hypertension) diseased patients developed higher amounts of ACE2 after ARB and ACEI treatments ). However, upon reviewing the literature, it was found that the higher amount of ACE2 secretion was due to conditions like myocardial infarction (Ishiyama et al. 2004; Burrell et al. 2005; Ocaranza et al. 2006 ) rather than the treatment with drugs for COVID-19 (Rossi et al. 2020) . It was found that the increased levels of ACE2 aided the blocking of 2019-nCoV attachment to the lung cells by jamming its S protein (Fig. 5) . This strategy was used in the development of anti-COVID-19 drugs to prevent the lung infection caused by 2019-nCoV (Kruse 2020; Zhang et al. 2020 ). This hypothesis was spread by various scientific societies such as the Italian Society of Arterial Hypertension, the Italian Society of Cardiology and the European Society of Hypertension (ESH) and encouraged the patients to continue their ARB-and ACEI-based treatments (Greene et al. 2013; Danser et al. 2020; Perico et al. 2020 ). In fact, it was found in a study that adverse health effects and clinical instability were observed in highrisk patients if the ARB and ACEI-based treatments were withdrawn abruptly (Vaduganathan et al. 2020 ).

The structure of 2019-nCoV consists of six open-reading frames (ORFs) which code for the synthesis of subgenomic mRNAs. The frameshift mutations amongst ORF1a and ORF1b are responsible for coding pp1a (486 kDa) and pp1ab (790 kDa) polyproteins (Muramatsu et al. 2016; Rana et al. 2020 ). These polyproteins are cleaved into functional proteins by papain-like protease (PLpro) and 3-chymotrypsin-like protease (3CLpro), also known as main protease (Mpro) (Ziebuhr et al. 2000) .

The main function of PLpro is to defend the coronavirus from immune reaction of the host by removing ubiquitin, whereas 3CLpro aids in the synthesis of functional proteins responsible for translation and replication of the virus. Plant-derived products (Akram et al. 2018) Chandel et al. 2020b ). Since 3CLpro and PLpro are essential for 2019-nCoV survival, these can be targeted as anti-COVID drugs (Han et al. 2005) . PLpro possesses papain-like cysteine protease characteristics, three self-cleaving sites and deubiquitinating activity (Barretto et al. 2005; Han et al. 2005) . It is known to hydrolyze synthetic ubiquitin peptide substrate, polyubiquitin and diubiquitin in vitro (Barretto et al. 2005; Lindner et al. 2005) . In a study, 6-thioguanine (6TG) and 6-mercaptopurine (6MP) were found to be slow-binding inhibitors of PLpro in 2019-nCoV (Chou et al. 2008 ) through allosteric inhibition which change the conformation of active site making it unavailable for binding. Like previous antiviral drug formulations (O'Connor and Roth 2005) , these compounds can be optimized as anti-COVID-19 drugs. However, these drugs can be cytotoxic to the patients if administered in higher dosages (Chou et al. 2008) .

3CLpro possesses a His41 which behaves as a basic acid-base during proteolysis and an active site with Cys145 (Liu and Zhou 2005) . TG-0205221 and chloromethyl ketone (CMK) (Anand et al. 2003) were first-generation 3CLpro inhibitors forming a covalent bond between the reactive atom and Cys145 (Anand et al. 2003; Xue et al. 2008 ) giving rise to a strong protease interaction. However, these drugs exhibit some adverse side effects such as lower potency, toxicity, and off-target reactions (Ghosh et al. 2010; Tuley and Fast 2018) . A strong inhibitory interaction was observed with the binding of Cm-FF-H, a peptide aldehyde inhibitor, to protease of 2019-nCoV. The ligand bound non-covalently to hydrophilic pocket of protease via its electrophilic P1-phenyl alanine residue (Zhu et al. 2011 ). This inhibitor explicated its inhibitory activity by catalyzing the conversion of trifluoromethylb-amino alcohol to four tetra-and triglutamic acid and glutamine peptides (Sydnes et al. 2006 ). Good to moderate inhibitory activity has been observed using tripeptidic Z-Val-Leu-Ala(pyrrolidone-3-yl)-2-benzothiazole (Hosseini-Zare et al. 2020). As the peptidyl inhibitors possess weaker pharmacokinetics profiles, impermeability to cell membranes and in vivo instability, caution should be taken while considering them as 3CLpro inhibitors.

COVID-19 is characterized by a highly conserved genomic organization, unique enzymatic activities, and expression of nonstructural genes by ribosomal frame-shifting (Fehr and Perlman 2015) . Mature SARS-CoV-2 virion reproduction depends on the host cellular mechanisms. A plausible therapeutic target to inhibit RNA replication from an RNA template which leads to three potential benefits as depicted in Fig. 6. Even though low-level nonstructural proteins (NSPS) production is still possible inside the cell, but eliminating the viral infection is only possible by targeting the RNA replication of the virus (Astuti and Ysrafil 2020) .

The genome of coronavirus includes a 5′ cap structure along with a 3′ poly (A) tail that serves as a mRNA for translation, and this is responsible for translation of the replicase polyproteins. Two-thirds of the genome is formed by the replicase gene which encodes the NSPS. Several accessory proteins have been shown to play a role in viral pathogenesis, but these are not essential for viral replication but are also included in the genome .

Once the viral genome enters the cytoplasm, the host ribosomes translate the viral positive-sense RNA into 16 NSPS that may be engaged in making sure that the viral RNA is translated efficiently without interference from the host. Some NSPS are vital for the production of mature virions, while the other NSPS develop the replicase-transcriptase complex (RTC) that consists of proteins needed to replicate both genomic and sub-genomic viral RNA through anti-sense RNA intermediates (Ziebuhr 2005) . The viral structural proteins enter the endoplasmic reticulum (ER) following viral genomic RNA replication and viral protein translation from sub-genomic RNA. The proteins then follow the secretory pathway and develop the endoplasmic reticulum-Golgi intermediate compartment (ERGIC). Following this formation, the N protein encapsulated viral RNA genomes get incorporated into the ERGIC, and then bud into mature virions which eventually exit the cell via exocytosis and infect other cells, thereby spreading the virus load (Choudhury et al. 2020) .

Besides treating the various symptoms of COVID-19, clinicians can opt for targeted treatment for the SARS-CoV-2 by targeting viral-specific processes such as viral replication through RdRp inhibition. This is a better approach as it stops the formation of mature virions and stops the virus from spreading and damaging other host cells (Warren et al. 2016; Siegel et al. 2017) .

Antiviral drugs that target the RdRp active sites such as the ASP760 and ASP761 may potentially serve as a therapeutic option. Anti-viral drugs such as Favipiravir are viral-specific, and they inhibit the RdRp and result in the inhibition of SARS-CoV-2. Favipiravir structurally has a carboxamide (C-[O]-NH2) moiety that targets the viral RNA polymerase, and its active form blocks the catalytic domain of the viral RNA-dependent RNA polymerase, and its enzymatic activity. This effectively ends the infectious cycle of SARS-CoV-2. Favipiravir is not toxic to mammalian cells since it does not inhibit RNA or DNA synthesis within mammalian cells (Holshue et al. 2020 ). 

In humans, transplantation of organs such as heart, lungs, liver and kidneys are being performed more frequently. In response to this transplantation, lifelong dual or triple immunosuppressive therapy is needed to prevent the organ rejection. COVID-19 has become a problem in solid-organ transplant (SOT) patients (Willicombe et al. 2020) and there is no clue to deal with immunosuppression in SOT recipients having COVID-19. Immunosuppressive drugs named as calcineurin inhibitors (CNIs), a calcium-calmodulinactivated serine/threonine-specific phosphatase, an immunosuppressive drug, which acts as an important inhibitor in the prevention of rejection. On the other hand, drugs named as cyclosporin and tacrolimus are helpful in transplantation of medicine in CNIs. (Hage et al. 2020) . Tanaka et al. (2013) studied that cyclosporin suppressed the replication process of SARS-CoV-1 which is another common virus of Severe Acute Respiratory Syndrome (SARS). Calcineurin inhibitors (CNIs) such as cyclosporin and its derivatives such as cyclosporine A-derivatives inhibit the calcineurin pathway by binding to cellular cyclophilins (Cyps) and NL63 is inhibited by cyclosporine A-derivatives (Carbajo-Lozoya et al. 2014; Sanchez-Pernaute et al. 2020) . Tacrolimus, another immunosuppressive drug, inhibits calcineurin by suppressing the early phase activation of T cells and expression of cytokines resulting in the suppression of immune-cellular responses, which lead to the prevention of blizzard of cytokines (IL-2, IL-4, TNF-α and IFN-γ) in COVID-19.

A cytokine is a signaling molecule responsible for the regulation of distinct biological functions via receptors present on the surface of the cell (Bartee and McFadden 2013) while chemokine is a specific cytokine for attracting the cells to the site of inflammation or infection. Cellular infection followed by viral replication leads to the release of proinflammatory cytokines and death of the cell resulting in an amplified inflammatory response due to release of damage-associated molecular pattern (Tay et al. 2020; Siu et al. 2019; Chen et al. 2019) . The exact nature of the inflammatory response depends upon the type of virus and the tissue that has been infected (Thomas et al. 2009; Allen et al. 2009 ). Cytokine Release Syndrome (CRS) or Cytokine storm is a condition of exaggerated release of cytokines after infection by a virus and it is emerging as a leading cause of Multiple Organ Failure (MOF) and Acute Respiratory Distress Syndrome (ARDS) in COVID-19 (Tay et al. 2020) .

Severely affected patients have been found to have raised levels of interleukins (IL): (IL)-1β, IL-2, IL-6, IL-7, IL-8, IL-9, IL-10, IL-18, TNF-α, Macrophage Colony-Stimulating Factor (M-CSF), Granulocyte Macrophage-Colony-Stimulating Factor (GM-CSF), Granulocyte-Colony-Stimulating Factor (G-CSF), 10 kD interferon-gamma-induced protein (IP-10), Macrophage Inflammatory Protein 1-α (MIP 1-α) and Monocyte Chemoattractant Protein-1 (MCP-1) in the serum (Huang et al. 2019; Liu et al. 2020; Wang et al. 2020) . These studies focused on the potential role of immunosuppressive or immunomodulatory approaches to combat unregulated proinflammatory response.

The COVID-19 infection involves three phases. It starts from an asymptomatic phase in which virus is shredded in high amount in the upper respiratory tract. In the second phase, which is the non-severe symptomatic phase, adaptive immune activation occurs which allows the development of B (generation of specific antibodies) and T cell responses (Fig. 7) . In approximately 80% of the patients, this phase marks the end of the disease. Final phase involves the release of high levels of inflammatory cytokines. This phase is also characterized by MOF, progressive fever, hypercoagulability and shock (Berlin et al. 2020) . Studies have shown that the inhibition of excessive inflammatory mechanisms contributes in eliminating the viral resistance. Immunomodulatory strategies involved in the treatment of COVID-19 infection targeting certain cytokines are listed in Table 3 .

The convalescent plasma of patients recovered from COVID-19 infection can be used to meet the requirements of antiviral antibodies in newly affected COVID-19 patients. Various beneficial actions of convalescent plasma can, therefore, be availed to help fight against new COVID-19 infection cases. Most viral illnesses manifest a viremia peak within the first week of infection, and it takes about 10-14 days for the host to develop a primary immune response that signals virus clearance. However, viral antibodies contained in convalescent plasma enable viremia suppression, especially if given at an early stage of the disease. Antibody-dependent cellular cytotoxicity (ADCC), complement activation and phagocytosis are also some of the mechanisms that come in effect to clear the virus load. Inflammatory-response suppression and coagulation factors restoration are also plausible mechanisms that help fight against the COVID-19 disease, especially when convalescent plasma is administered early, even to asymptomatic cases (Gunn et al. 2018; Van Erp et al. 2019 ).

US FDA has given the approval for the use of COVID-19 convalescent plasma in COVID-19 patients who are at a serious or immediate life-threatening stage of the disease on March 24, 2020. Only certified blood laboratories and technicians should collect plasma with proper approved equipment. The volume of the plasma collected at any one time can be between 200 and 600 ml, with a gap of at least 7 days before another collection from the same donor. Donors eligible to give convalescent plasma are defined as meeting the following criteria: (1) recovered COVID-19 patients that were COVID-19 positive either a positive nasopharyngeal 

Convalescent plasma transfusion is generally considered to be safe and without serious adverse effects. However, the risk of TRALI should be kept in mind, and donor selection criteria should be adhered to, meticulously. After getting an informed consent from the patient, convalescent plasma should be given to COVID-19 positive patients who have severe disease symptoms as defined by the following criteria like respiratory rate should be ≥ 30/min whereas blood oxygen saturation must be ≤ 93%. On the other hand, the ratio of partial pressure of arterial oxygen to fraction of inspired oxygen ratio should be less than 300 otherwise, it may lead to life-threatening disease conditions such as respiratory failure, septic shock, or multiple organ dysfunction (Franchini et al. 2020 ).

More than 15,521,145 patients have already recovered from COVID-19 globally by 19 September 2020. The convalescent plasma is definitely a powerful life-saving therapeutic option for newly affected COVID-19 patients. In addition, more donors can also be channeled for providing therapy, if they are asymptomatic but antibody-positive. Convalescent plasma administration within 10-11 days after symptoms, may result in a quick rise in lymphocyte counts, diminished CRP levels, and an obvious resolution of lung lesions of CT scans. Results obtained from convalescent plasma administration have been considered to be promising without any serious adverse effects. Convalescent plasma administration should be given as early as possible to severe cases to maximize its efficacy which could certainly alter the morbidity and mortality burden associated with the COVID-19 pandemic (Chang et al. 2020a, b; Chen et al. 2020 ).

From the past hundreds of years, the SARS virus has been proved to be the greatest worldwide public health crisis. The present century also became the victim of SARS-CoV-2 causing the disease popularly known as COVID-19. Till now there are approximately more than 10 million of people have suffered from this disease and lost their lives. The literature proved that there is no proper vaccine and drugs for the treatment of virus. Various in vitro and in silico studies should be considered and given a due attention to eradicate COVID-19. The in vitro data in most cases has been proved to be beneficial but more drugs and vaccine candidates should be studied and taken under consideration for future pandemic. Preventive measures need to be strictly adopted by the population across the world to protect themselves from the current pandemic. Combination of drugs and various inhibitors for blocking the entry and replication process should be considered. Simultaneously, identification of new treatment modalities needs to be investigated. Proper sharing of resources and knowledgeable information could prove to be helpful in fighting this deadly coronavirus disease. Present review will definitely lead us to understand the complexities of this disease and to design novel and potent drugs along with inhibitors against SARS-CoV-2.

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Functional activity of CXCL8 receptors, CXCR1 and CXCR2, on human malignant melanoma progression

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

Severe acute respiratory syndrome coronavirus papain-like novel protease inhibitors: design, synthesis, protein−ligand X-ray structure and biological evaluation

Phenylarsine oxide inhibition of endocytosis: effects on asialofetuin internalization

COVID-19: drug targets and potential treatments

Haemoconcentration, renal function, and post-discharge outcomes among patients hospitalized for heart failure with reduced ejection fraction: insights from the EVEREST trial

Compassionate use of remdesivir for patients with severe Covid-19

A role for Fc function in therapeutic monoclonal antibody-mediated protection against Ebola virus

Pathogenetic mechanisms of severe acute respiratory syndrome

Angiotensin-converting enzyme 2-independent action of presumed angiotensin-converting enzyme 2 activators: studies in vivo, ex vivo and in vitro

Calcineurin inhibitors in COVID-19-lessons learnt from transplantation medicine

Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis

Papain-like protease 2 (PLP2) from severe acute respiratory syndrome coronavirus (SARS-CoV): expression, purification, characterization and inhibition

TMPRSS2 and ADAM17 cleave ACE2 differentially and only proteolysis by TMPRSS2 augments entry driven by the severe acute respiratory syndrome coronavirus spike protein

From SARS to MERS: crystallographic studies on coronaviral proteases enable antiviral drug design

Continuous regional arterial infusion versus intravenous administration of the protease inhibitor nafamostat mesilate for predicted severe acute pancreatitis: a multicenter, randomized, open-label, phase 2 trial

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

First case of 2019 novel coronavirus in the United States

Targeting severe acute respiratory syndrome-coronavirus (SARS-CoV-1) with structurally diverse inhibitors: a comprehensive review

Inhibition of IFN-γ signaling by glucocorticoids

Clinical features of patients infected with 2019 novel coronavirus in

Angiotensin-converting enzyme 2 protects from severe acute lung failure

Clathrin-dependent entry of severe acute respiratory syndrome coronavirus into target cells expressing ACE2 with the cytoplasmic tail deleted

Upregulation of angiotensin-converting enzyme 2 after myocardial infarction by blockade of angiotensin II receptors

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

The ambiguous base-pairing and high substrate efficiency of T-705 (favipiravir) ribofuranosyl 5′-triphosphate towards influenza A virus polymerase

A rapid advice guideline for the diagnosis and treatment of 2019 novel coronavirus (2019-nCoV) infected pneumonia (standard version)

PubChem substance and compound databases

Therapeutic strategies in an outbreak scenario to treat the novel coronavirus originating in Wuhan, China

A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury

Identification of phytochemical inhibitors against main protease of COVID-19 using molecular modeling approaches

Race to find COVID-19 treatments accelerates

Regulation of the formation of tumor cell pseudopodia by the Na (+)/H (+) exchanger NHE1

Depletion of intracellular potassium arrests coated pit formation and receptor-mediated endocytosis in fibroblasts

The papain-like protease from the severe acute respiratory syndrome coronavirus is a deubiquitinating enzyme

SARS-CoV protease inhibitors design using virtual screening method from natural products libraries

A dominant-negative clathrin mutant differentially affects trafficking of molecules with distinct sorting motifs in the class II major histocompatibility complex (MHC) pathway

Clinical characteristics of novel coronavirus cases in tertiary hospitals in Hubei Province

Functions of T cells in asthma: more than just TH 2 cells

Dynasore, a cell-permeable inhibitor of dynamin

Therapeutic development and drugs for the treatment of COVID-19

The coronavirus nucleocapsid is a multifunctional protein

Safety, tolerability, pharmacokinetics, and pharmacodynamics of single-dose antiinterleukin-18 mAb GSK1070806 in healthy and obese subjects

A randomized, controlled trial of Ebola virus disease therapeutics

COVID-19 vaccine development pipeline gears up

Molecular targets for COVID-19 drug development: enlightening Nigerians about the pandemic and future treatment

SARS-CoV 3CL protease cleaves its C-terminal autoprocessing site by novel subsite cooperativity

Enalapril attenuates downregulation of angiotensin-converting enzyme 2 in the late phase of ventricular dysfunction in myocardial infarcted rat

Finding new tricks for old drugs: an efficient route for public-sector drug discovery

A randomized, controlled trial to evaluate the effect of an anti-interleukin-9 monoclonal antibody in adults with uncontrolled asthma

Angiotensin converting enzyme 2 gene expression increased compensatory for left ventricular remodeling in patients with end-stage heart failure

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

Should COVID-19 concern nephrologists? Why and to what extent? The emerging impasse of angiotensin blockade

Drug targets for corona virus: a systematic review

Endosomal proteolysis by cathepsins is necessary for murine coronavirus mouse hepatitis virus type 2 spike-mediated entry

Understanding the Molecular Mechanism(s) of SARS-CoV2 Infection and propagation in human to discover potential preventive and therapeutic approach

Virtual screening of naturally occurring antiviral molecules for SARS-CoV-2 mitigation using docking tool on multiple molecular targets

Potential harmful effects of discontinuing ACE-inhibitors and ARBs in COVID-19 patients

Cyclosporine therapy during the COVID-19 pandemic is not a reason for concern

Efficacy of camostat mesilate against dyspepsia associated with non-alcoholic mild pancreatic disease

Animal coronaviruses: what can they teach us about the severe acute respiratory syndrome?

Structural basis of severe acute respiratory syndrome coronavirus ADP-ribose-1″-phosphate dephosphorylation by a conserved domain of nsP3

Why choose cyclosporin A as first-line therapy in COVID-19 pneumonia

The ACE2/angiotensin-(1-7)/MAS axis of the renin-angiotensin system: focus on angiotensin

Drug targets for COVID-19 therapeutics: ongoing global efforts

Amantadine and dansylcadaverine inhibit vesicular stomatitis virus uptake and receptor-mediated endocytosis of alpha 2-macroglobulin

Tocilizumab: a review in rheumatoid arthritis

Interleukin-1 receptor blockade is associated with reduced mortality in sepsis patients with features of the macrophage activation syndrome: re-analysis of a prior phase III trial

] adenine c-nucleoside (gs-5734) for the treatment of Ebola and emerging viruses

Coronavirus disease 2019 drug discovery through molecular docking

Experimental treatment with favipiravir for Ebola virus disease (The JIKI Trial): a historically controlled, single-arm proof-of concept trial in Guinea

Severe acute respiratory syndrome coronavirus ORF3a protein activates the NLRP3 inflammasome by promoting TRAF3-dependent ubiquitination of ASC

COVID-19 pandemic: from molecular biology, pathogenesis, detection and treatment to global societal impact

Circulating ACE2 activity is increased in patients with type 1 diabetes and vascular complications

COVID-19: combining antiviral and anti-inflammatory treatments

Synthesis of glutamic acid and glutamine peptides possessing a trifluoromethyl ketone group as SARS-CoV 3CL protease inhibitors

Ayurveda and allopathic therapeutic strategies in coronavirus pandemic treatment 2020

Suppression of coronavirus replication by cyclophilin inhibitors

The trinity of COVID-19: immunity, inflammation and intervention

The intracellular sensor NLRP3 mediates key innate and healing responses to influenza A virus via the regulation of caspase-1

The taxonomy of covalent inhibitors

Targeting proteases: successes, failures and future prospects

Canakinumab in a subgroup of patients with COVID-19

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

COVID-19 in republic of India: A report on situation and precautionary strategies to global pandemic

Solomon SD (2020) Renin-angiotensin-aldosterone system inhibitors in patients with Covid-19

Mutations in human dynamin block an intermediate stage in coated vesicle formation

Fcmediated antibody effector functions during respiratory syncytial virus infection and disease

Hydrolysis of biological peptides by human angiotensin-converting enzymerelated carboxypeptidase

Chloroquine is a potent inhibitor of SARS coronavirus infection and spread

Role of the clathrin terminal domain in regulating coated pit dynamics revealed by small molecule inhibition

Stilbene-based natural compounds as promising drug candidates against COVID-19

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

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

COVID-19 and calcineurin inhibitors: should they get left out in the storm?

Acute respiratory distress syndrome leads to reduced ratio of ACE/ACE2 activities and is prevented by angiotensin-(1-7) or an angiotensin II receptor antagonist

Effective treatment of severe COVID-19 patients with tocilizumab

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

Ageand gender-related difference of ACE2 expression in rat lung

Structures of two coronavirus main proteases: implications for substrate binding and antiviral drug design

Identification of nafamostat as a potent inhibitor of middle east respiratory syndrome coronavirus S protein mediated membrane fusion using the split-protein-based cell-cell fusion assay

The serine protease inhibitor camostat inhibits influenza virus replication and cytokine production in primary cultures of human tracheal epithelial cells

Targeting the endocytic pathway and autophagy process as a novel therapeutic strategy in COVID-19

Drug design targeting the main protease, the Achilles' heel of coronaviruses

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

Expression of auxilin or AP180 inhibits endocytosis by mislocalizingclathrin: evidence for formation of nascent pits containing AP1 or AP2 but not clathrin

Protease inhibitors targeting coronavirus and filovirus entry

Peptide aldehyde inhibitors challenge the substrate specificity of the SARS-coronavirus main protease

The coronavirus replicase

Virus-encoded proteinases and proteolytic processing in the Nidovirales

The authors are grateful to the Maharishi Mar-