key: cord-1044546-qcofy3kz
authors: Suganya, Sakthivel; Divya, Suresh; Parani, Madasamy
title: Severe acute respiratory syndrome‐coronavirus‐2: Current advances in therapeutic targets and drug development
date: 2020-09-23
journal: Rev Med Virol
DOI: 10.1002/rmv.2174
sha: 4391eef0dcff27a11101b83c073a10f130aa396a
doc_id: 1044546
cord_uid: qcofy3kz

The current pandemic of severe acute respiratory syndrome‐coronavirus‐2 (SARS‐CoV‐2) has quickly emerged as a global health concern with government bodies worldwide taking drastic control measures. Understanding the virology of SARS‐CoV‐2, its molecular mechanisms, and its pathogenesis are required for a targeted therapeutic approach. In this review, we highlight the current molecular and drug advances that target SARS‐CoV‐2 at the genome level. We also summarize studies that therapeutically target the host angiotensin‐converting enzyme 2 and proteases. Finally, we summarize antibody‐mediated therapeutic approaches, as well as recent trends in vaccine development. Hence, the purpose of this study is to investigate different molecular targets in SARS‐CoV‐2 pathogenesis and their usefulness in developing strategies for drug development.

The current pandemic of severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) has quickly emerged as a global health concern with government bodies worldwide taking drastic control measures. Understanding the virology of SARS-CoV-2, its molecular mechanisms, and its pathogenesis are required for a targeted therapeutic approach. In this review, we highlight the current molecular and drug advances that target SARS-CoV-2 at the genome level. We also summarize studies that therapeutically target the host angiotensin-converting enzyme 2 and proteases. Finally, we summarize antibody-mediated therapeutic approaches, as well as recent trends in vaccine development. Hence, the purpose of this study is to investigate different molecular targets in SARS-CoV-2 pathogenesis and their usefulness in developing strategies for drug development. 118,000 and causing 4292 deaths, so that the World Health Organization (WHO) pronounced it a pandemic disease. 3 The WHO strategized to break human-human transmission by quarantining patients at an earlier stage, recognizing and reducing transmission from animal sources, and promoting research and vaccine development. 4 Severe social and economic impacts were felt amidst the struggle against the deadly virus. Despite the precautionary measures across different countries, SARS-CoV-2 had infected more than 13.8 million individuals by July 2020, causing 597,000 deaths worldwide. 5 SARS-CoV-2, a 29.8 Kb positive-sense single-stranded RNA virus, shares more than 70% sequence homology with SARS-CoV. 6 Despite its similarity with SARS-CoV, its transmission competency and complexity are different. Investigations suggest that the contagious SARS-CoV-2 virus spread from human to human via respiratory droplet transmission from coughing or sneezing. 7 Recently, the WHO Abbreviations: ACE2, angiotensin-converting enzyme 2; Ang 1-7, angiotensin 1-7; Ang 1-9, angiotensin 1-9; Ang I, angiotensin I; Ang II, angiotensin II; ARDS, acute respiratory distress syndrome; AT1, angiotensin II type 1; AT2, angiotensin II type 2; CDE, Centre for Drug Evaluation; Covid-19, coronavirus disease 2019; CP, convalescent plasma; FDA, Food and Drug Administration; HCoV, human coronavirus; hrsACE2, human recombinant soluble ACE2; MERS-CoV, Middle East respiratory syndrome-coronavirus; M pro , main protease; NAbs, neutralizing antibodies; nsps, non-structural proteins; PL Pro , papain-like protease; RAS, renin-angiotensin system; RBD, receptor binding domain; RdRp, RNA-dependent RNA polymerase; rhACE2, recombinant ACE2; SARS-CoV, severe acute respiratory syndrome coronavirus; SARS-CoV-2, severe acute respiratory syndrome-coronavirus-2; TMPRSS2, transmembrane protease serine 2; WHO, World Health Organization. has also announced airborne and aerosol as one possible mode of transmission of SARS-CoV-2. 8, 9 The average incubation period, which is the duration between viral exposure and symptom onset, is estimated to range from 5 to 6 days, however; it can go up to 14 days in some cases. [10] [11] [12] Mostly, affected individuals experience mild symptoms, comprised of high body temperature in conjunction with symptoms such as fatigue, cough, diarrhoea, sore throat and headache. 13 Some patients experience pneumonia and acute respiratory distress syndrome (ARDS). Individuals with underlying health complications such as heart disease, chronic pulmonary disease and diabetes develop more severe symptoms. 14 Numerous investigations on SARS-CoV-2 focus on delineating potential therapeutic targets, identifying viral inhibitors and re- 

The genome of SARS-CoV-2 codes for non-structural proteins (nsps), structural proteins and accessory proteins, all of which mediate viral maintenance, replication and life cycle. The ORF 1a and ORF 1b coding for the polyproteins pp1a and pp1ab make up about twothirds of the whole genome 18 ( Figure 1A ). These polyproteins are processed into 16 nsps (nsp1-16) by the main protease (M pro ) and the Papain-like protease (PL Pro ). 19 ORFs occupying one-third of the genome encode structural proteins such as spike (S), membrane (M), envelope (E) and nucleocapsid (N) proteins. The ORF3, ORF6, ORF7 and ORF8 genes encode 6-9 accessory proteins. 20 Recent studies employed different strategies to inhibit viral pathogenesis by targeting nsps and structural proteins, combating the progression of viral replication and life cycle progression inside host cells.

Since viral proteases mediate the generation of mature nsps, inhibiting the proteolytic functions of M pro and PL Pro might halt the production of mature nsps. Drugs that target M pro may decrease the risk of drug resistance, which results from mutations and might exhibit wide spectrum antiviral activity. 21 The SARS-CoV-2 M pro inhibitor 11a showed a high inhibition rate and good pharmacokinetic properties. 19 While studies have seldom focused on the M protein of SARS-CoV-2 as a drug target, the E and N proteins have been understood to have critical functions. The E proteins form ion channels, rendering a crucial role in the assembly of viral particles and pathogenesis inside the host. 33 Molecular docking studies report that the antivirals glecaprevir, saquinavir, simeprevir might inhibit SARS-CoV-2 and reduce pathogenicity. 34, 35 Recent studies have targeted the N proteins with pre-existing FDA approved drugs and re-purposed anti-human coronavirus (HCoV) drug combinations such as sirolimus with dactinomycin, mercaptopurine with melatonin, and toremifene with emodin to shorten the viral life cycle inside the host. 36 Due to the evolutionarily conserved nature of the N protein sequence (∼90% with SARS-CoV) and its contribution to high immunogenicity and abundant expression in infected people, it is one of the vaccine candidates that is highly studied. 37 

The primary dependency of SARS-CoV-2 on the ACE2 receptor has necessitated a detailed understanding of ACE2 downstream functions. Because its discovery over 20 years ago, ACE2 has been recognized as a crucial determinant of the renin-angiotensin system (RAS). 38, 39 The harmful effects of the ACE/RAS pathway are counterbalanced via the ACE2/Ang1-7/MAS axis. 40 The ACE/RAS pathway is initiated upon the formation of active renin from an inactive precursor prorenin (Mr 46,000 protein). The renin released in blood cleaves angiotensinogen into Ang I (angiotensin I) ( Figure   1B ). Physiologically dormant Ang I acts as a precursor of active Ang II (angiotensin II). Binding of Ang II to AT1 and AT2 (Angiotensin 

The AT1 receptor antagonist drugs losartan, telmisartan and olmesartan have been widely used in hypertensive patients since the 1990s since their adverse effects are rare. 47 The AT1 receptor antagonists elevate ACE2 expression in rats and humans. Currently, losartan and telmisartan are under phase II clinical trial for SARS-CoV2 infection. [48] [49] [50] While recombinant ACE2 can be an additional target, studies claim that a recombinant ACE2 (rhACE2) lacks the membrane-anchored domain, thus becoming soluble inside the cell. [51] [52] [53] Recently, the Centre for Drug Evaluation (CDE), China, ended a clinical trial for rhACE2 due to its lack of statistically significant effect as a drug treatment approach against SARS-CoV2. 54, 55 However, scientists have identified a genetically altered human recombinant soluble ACE2 (hrsACE2), which showed a dose-dependent effect on SARS-CoV-2 viral replication in cell culture studies, and a reduced viral entry by a factor of 1000 to 5000. 56 Despite these benefits, hrsACE2 is not a favoured drug for clinical use because it is a glycosylated protein, and its production will require additional effort, time, and cost, which is not advantageous in drug development. 57 Apart from ATI receptor blockers and recombinant ACE2, molecular docking studies revealed that two selected phytochemicals, 6-α-acetoxygedunin and echitamine, showed optimum binding to the human ACE2 receptor, which efficiently blocked the receptor and inhibited receptor-mediated SAR-CoV2 entry. 58 This preliminary evidence highlights the need for a comprehensive analysis of phytochemicals in an in vivo setting. Interestingly, a recent study by Minato et al. 59 showed that B38-CAP, a protein from Paenibacillus, had ACE2-like enzyme activity and decreased the Ang II levels in mice. Most importantly, recombinant B38-CAP protein converted Ang II to Ang 1-7 and contributed to the other ACE2 targeted functions. This study highlighted the functional similarity between bacterial B38-CAP and human ACE2 and B38-CAP is expected to undergo phase I clinical trial shortly. 57 Taken together, the studies mentioned above offer evidence that the ACE2 receptor is one of the leading potential targets against SARS-CoV-2.

Understanding the downsides of ACE2 might minimize the unexpected complications that may arise from ACE2 targeted drugs when used against SARS-CoV-2 infection. Stawiski et al. 60 identified variants in ACE2 receptors that modify virus-host interaction and significantly alter the host's vulnerability to SARS-CoV-2. They have deciphered 298 unique variants among 256 codons distributed through 805 amino acid residues of the human ACE2 receptor. 61 The understanding that the natural variations of the ACE2 receptor in human populations may alter ACE2 receptor binding affinity to SARS-CoV-2 S-protein produces divergent evidence regarding virus susceptibility. Additionally, ACE2 expression had a decreasing effect in aged individuals, to a greater extent in males than in females. 62 Diseases like diabetes mellitus reduce ACE2 expression, causing ACE2 deficiency. Though Ang 1-7 has a shielding effect against ARDS, enhanced Ang 1-7 formation from ACE2 in different organs (heart, kidney and vessels) might not render a protective outcome.

Patients with diabetes who were treated with pioglitazone, glucagonlike peptide-1 agonists and mineralocorticoid inhibitors showed increased endogenous ACE2 levels. 63 Hence, the combined use of these diabetic drugs and ATI receptor blocker/recombinant ACE2/ B38-CAP might cause a decrease in cytosolic pH and an increase in viral load, resulting in exacerbation of SARS-CoV-2 infection and mortality. 64 Collective considerations provide essential insights into the ACE2 receptor as potential therapeutic targets; however, the downsides of ACE2 highlights the requirement for additional targets to attenuate SARS-CoV-2 infection significantly.

Following the recognition of the ACE2 receptor by the S1 receptor binding domain (RBD) of SARS-CoV-2, the spike protein undergoes proteolytic activation by host proteases, causing cleavage of S1/S2 and S2, and fusion of viral particles with cellular membranes. 65 Upon entry of SARS-CoV-2, activation of host cell surface proteases [e.g., transmembrane protease serine 2 (TMPRSS2)] and lysosomal proteases (e.g., cathepsins L/B) contribute to severe symptoms and fatality in some infected patients. 66, 67 While these two kinds of proteases were actively investigated recently, furin and other proteases were also shown to contribute to the cumulative action of SARS-CoV-2. 65 The findings on TMPRSS2 stem from the earlier studies on influenza H1N1 and SARS-CoV outbreak, wherein this protease exhibited a similar mechanism to advance disease pathogenesis. 68 Therefore, researchers recommend the existing clinically proven TMPRSS2 inhibitors such as camostat, bromhexine, aprotinin, nafamostat to potentially combat SARS-CoV-2 infection. 69 Importantly, camostat has advanced to phase I clinical trial in March 2020, as one of the SARS-CoV-2 targets. 70, 71 Similarly, many pre-existing cathepsin inhibitors like K11777, oxocarbazate, MDL28170, and E-64d were studied for their effectiveness against SARS-CoV-2. [72] [73] [74] [75] [76] Dexamethasone, a corticosteroid approved by FDA in 1958 as a broad-spectrum immunosuppressor, is one of the cathepsin L/B inhibitors that has been approved by WHO to treat critically ill Covid-19 patients. 77, 78 One concern about using such inhibitors of host proteases may be the loss of function of innate TMPRSS2 and cathepsin L/B responses, which might result in side effects. Targeting TMPRSS2 and cathepsin L/B host protease at the same time using inhibitors might reduce the entry of the SARS-CoV-2 virus into host cells, thereby decreasing the viral load.

Neutralizing antibodies (NAbs) produced as a humoral response from the adaptive immune system bind to the viral epitope, preventing viral epitope-human receptor attachment and initiating viral lysis by antibody-mediated opsonisation or complement activation 79, 80 ( Figure 1C) . Interestingly, 95%-100% of SARS-CoV-2 infected Especially, the lung injury observed in a few Covid-19 patients indicates a cytokine storm reaction that progressed to ARDS aggravation, causing multi-organ failure and death. 84, 85 Therapeutic deployment of NAbs against SARS-CoV-2 is an important area of research that will likely contribute to controlling the pandemic and the potential re-emergence of viruses in the future.

Among SARS-CoV-2 targeted therapies, monoclonal antibodies (mAbs) may be efficient in providing immediate protection. Human monoclonal antibodies were studied against SARS-CoV during the epidemic in 2002-2004. 86, 87 Genetic similarity between SARS-CoV and SARS-CoV-2 led the researchers to check for the cross-reactivity of SARS-CoV mAbs in SARS-CoV-2 infected samples. 88 Notably, the RBD-specific mAbs, CR3022 and S309, cross-reacted efficiently with the SARS-CoV-2 S1 B RBD residues 318-510 and 337-444, respectively, without overlapping with ACE2 receptor binding sites. 89 However, mAbs, which can cross-react with the crucial SARS-CoV-2 S1 B RBD residues 460-492, may be considered critical for achieving a therapeutically beneficial outcome. The above-mentioned critical residues are only 50% conserved between both viruses, entailing the need to develop mAbs that are specific to SARS-CoV-2 RBD. 90, 91 Most importantly, a recent study reported the first human mAbs, 47D11, that neutralizes SARS-CoV-2 by binding to S1 B RBD, similar to CR3022 and S309, establishing its capacity to cross-neutralize SARS-CoV as well. 92 The beneficial effect of mAb 47D11 was demonstrated in HEK-293T cells, which was independent of receptor-binding inhibition. 93 AbbVie, an American biotech company, has collaborated with this research team to support further preclinical activities and human trials on mAb 47D11. 94 The major limitation of mAbs is the cost;

antibody-based drug treatment is more expensive than vaccines.

Convalescent plasma (CP) therapy, an approach of passive immunization by infusion of blood plasma from recovered patients into infected individuals, is also being explored in several countries. CP therapy acquired its popularity because of its use against SARS-CoV, MERS, H1NI and Ebola viruses in the past. 95 Currently, based on nonrandomized studies, the FDA has given emergency approval to CP therapy as a treatment option, which is mainly deployed in critically ill SARS-CoV-2 patients to reduce the viral load and mortality rate. 96 The challenges of CP therapy include the age and state of health of the donor, variations from unit to unit, informed consent from patients, and shortage of plasma. 97 Post-CP-therapy complications such as the transmission of other viruses, fever, chills, allergic reactions, acute lung injury, fluid overload and haemolytic events also need to be considered before opting for this treatment option. 98

Vaccination is defined as an active immunization technique whereby immunity against SARS-CoV-2 virus is induced in subjects artificially through exposure to antigens of the virus. 99 On 11 February 2020, the WHO announced that it would take approximately 18 months for a vaccine to become available to the public. 100 Currently, SARS-CoV-2

vaccines are under development using approaches like an inactivated virus, antigen presentation through viral vectors, recombinant vaccines, and DNA/mRNA vaccines. 101 As of July 2020, around 219

vaccines are under development worldwide, with 30 vaccines in human trials, including two in phase III clinical trial, two in phase II/III efficacy and dose-testing trials, two in phase II trials, 10 in phases I-II safety and efficacy trials, and fourteen in phase I trials (Table 1) . 102 to bring under control the SARS-CoV-2 pandemic. 106 

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We acknowledge the funding provided by SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu, India. Sakthivel Suganya and Suresh Divya would like to thank Dr. Ang Chin-Siang for his valuable support regarding this manuscript and Hsuan Lin for his comments on this manuscript.

The authors have no competing interest.

Sakthivel Suganya, Suresh Divya and Madasamy Parani wrote the manuscript. Sakthivel Suganya and Suresh Divya contributed equally to the manuscript.

https://orcid.org/0000-0002-3854-2353Madasamy Parani https://orcid.org/0000-0002-2265-1715