key: cord-0874211-bblbqqbb
authors: Servidio, Camilla; Stellacci, Francesco
title: Therapeutic approaches against coronaviruses acute respiratory syndrome
date: 2020-12-30
journal: Pharmacol Res Perspect
DOI: 10.1002/prp2.691
sha: 91d9dbde94ae52ce5bc4c1139f8005b225f9dd47
doc_id: 874211
cord_uid: bblbqqbb

Coronaviruses represent global health threat. In this century, they have already caused two epidemics and one serious pandemic. Although, at present, there are no approved drugs and therapies for the treatment and prevention of human coronaviruses, several agents, FDA‐approved, and preclinical, have shown in vitro and/or in vivo antiviral activity. An in‐depth analysis of the current situation leads to the identification of several potential drugs that could have an impact on the fight against coronaviruses infections. In this review, we discuss the virology of human coronaviruses highlighting the main biological targets and summarize the current state‐of‐the‐art of possible therapeutic options to inhibit coronaviruses infections. We mostly focus on FDA‐approved and preclinical drugs targeting viral conserved elements.

immunosuppressed patients. 8 The other three species, SARS-CoV, MERS-CoV, and SARS-CoV-2, are associated with severe respiratory infections and multiple organ failures, causing considerable global health emergencies. [9] [10] [11] [12] SARS-CoV is the causative agent of the severe acute respiratory syndrome epidemic in China from November 2002 to July 2003 that caused 15% mortality in infected patients. 13 MERS-CoV is the etiologic agent of the severe acute respiratory syndrome outbreak that emerged in the Middle East in 2012 with a significant case fatality rate of ~34%. 14 SARS-CoV-2, like MERS-CoV and SARS-CoV, attacks the respiratory tract but it seems to cause infections with different clinical manifestations ranging from mild respiratory diseases to interstitial pneumonia with a consequent lower fatality rate. 15, 16 Current data indicate that it has a higher transmissibility compared to SARS-CoV. 17 All the pathogenic human CoVs are thought to be emerged from animal reservoirs, probably from the spillover of bats to intermediate animal hosts leading then to animal-human cross-species transmission. 14, [18] [19] [20] [21] Alarmingly, due to the presence of several CoVs strains in animal reservoirs and their frequent recombination, interspecies jumping and new potential outbreaks are likely to emerge from time to time in the future and, for these reasons, effective drugs and therapies are clearly needed in order to fight present and future pathogenic infections. 22, 23 At present, there are no approved drugs and therapies for the treatment and prevention of human CoVs. Although several pharmaceutical industries and research groups are working on the discovery and the development of new drugs and vaccines, drug development is a slow process that requires several years. Given the current emergency, the main adopted strategy regards the repurposing of FDA-approved drugs like antivirals approved for treating infections caused by influenza virus, HIV, hepatitis virus, etc., immunomodulatory agents and so on. [24] [25] [26] In this review, we discuss first the biology of the human pathogenic MERS-CoV, SARS-CoV, and SARS-CoV-2 highlighting the different biological targets that can be exploited for the design and development of antiviral drugs. Then, we summarize the current state of the art of possible therapeutic options to inhibit viral infections, focusing on both FDA-approved and preclinical drugs, dividing them into three main classes on the basis of the biological target. Therapeutic approaches aimed to alleviate symptomatology of CoVs infections are out of the scope and will not be reviewed. SARS-CoV-2 shares 79% sequence identity at genomic level with SARS-CoV, whereas it is more distant from MERS-CoV (approximately 50% of sequence conservation). 27 Despite their genomic diversity, all CoVs share the same genome organization ( Figure 1 ). The 5' terminal encodes a polyprotein, pp1ab, that is then processed by two viral proteases, the 3C-like protease (3CL pro ) and the papain viral protease (PLpro) into non-structural proteins involved in replication and transcription processes, like RNA-dependent RNA polymerase (RdRp) and helicase. On the other hand, within the 3' terminal are encoded four typical coronaviral structural proteins in the following order: the spike glycoprotein (S), the envelope protein (E), the membrane protein (M), and the nucleocapsid protein (N); moreover, from this terminal are encoded also accessory proteins that are thought to affect the host immune response. 5, 7, [27] [28] [29] [30] Among the structural proteins, the spike glycoprotein is particularly interesting since it mediates host-cell entry utilizing specific host receptors: angiotensin-converting enzyme 2 (ACE2) for SARS-CoV and SARS-CoV-2, and dipeptydil peptidase 4 (DPP4) for MERS-CoV. [31] [32] [33] The host receptors are the main determinant of the pathogenesis and the tissue and cellular tropism of viruses. 17, 34, 35 F I G U R E 1 Illustration of coronaviruses general structure (a) [5] and genomic organization (b). Viral particle image adapted with permission from Spinger Nature | 3 of 21 ACE2 is an ectoenzyme involved in the regulation of the reninangiotensin system that is expressed at high levels in lungs, kidneys, heart, and gastrointestinal tract. 36, 37 A significative overexpression of ACE2 has been reported in different airway epithelial cell types, in particular in alveolar and nasal epithelial cells, consistent with the pathogenesis and viral transmissibility of SARS-CoV and SARS-CoV-2. 38 However, although ACE2 is involved in viral entry for SARS-CoV and SARS-CoV-2, transgenic mouse models lacking ACE2 appear to suffer much worse disease pathogenesis when subjected to mechanical and chemical lung injury. 39 In this regard, in vitro and in vivo studies have revealed that SARS-CoV causes a downregulation of ACE2 expression that contributes to a worsening of lung injury severity. 40 DPP4 is a transmembrane ectoenzyme expressed in different tissues like kidney, gastrointestinal tract, and hematopoietic cells.

Regarding the respiratory tract, DPP4 showed a lower level of expression in nasal epithelial cells compared to alveolar cells, consistent with the pathogenesis and lower transmissibility of MERS-CoV compared to SARS-CoV and SARS-CoV-2. 41 Furthermore, an overexpression of DPP4 in alveolar cells seems to be in patients with chronic respiratory diseases.

CoVs enter host cells mainly through receptor-mediated endocytosis. 13 Since CoVs spike proteins are class I viral fusion proteins, protease cleavage is essential for their activation and, consequently, for viral entry. Depending on virus species, several cellular proteases are implicated in this process; the transmembrane protease serine 2 (TMPRSS2) is required for the activation of several CoVs spike proteins including SARS-CoV, MERS-CoV, and SARS-CoV-2. [42] [43] [44] However, in many cases, also other cellular proteases are necessary for viral entry. Therefore, for the activation of MERS-CoV and probably SARS-CoV-2 spike protein, is firstly required a furin-mediated cleavage, a serine protease involved in the host-cell entry of different RNA viruses such as EBOV or HIV. 45, 46 In this context, cathepsin-dependent pathways seem to contribute to viral entry and intracellular trafficking. In support of this, several cathepsin inhibitors have shown to reduce viral entry and infections such as antimicrobial and antimalarial drugs. 47, 48 Once inside, the genomic RNA is transcribed and translated, and the new assembled virions are released extracellularly by exocytosis. 49 

Despite their genomic diversity, CoVs lifecycle steps share key biological elements, with a certain homology between different CoVs strains, that can be exploited for the design and development of antiviral drugs; promising biological elements include: RNA-dependent RNA polymerase, the two viral proteases 3CL pro and PL pro , the spike glycoprotein and, finally, the cellular proteases involved in viral entry, such as TMPRSS2 and cathepsins. 50 Although, currently, there are no approved drugs and therapies for the treatment and prevention of human CoVs, several agents, FDA-approved and preclinical, that target key viral conserved elements, have shown in vitro (Table 1 ) and in vivo antiviral activity, becoming potential drugs to use to fight CoVs infections. However, some of them used clinically during SARS, MERS, and Covid-19 outbreaks did not show any beneficial results.

In the light of this, in this review we summarize the current state of possible therapeutic approaches to inhibit viral infections, investigating both FDA-approved and preclinical drugs, and depending on the biological target, we will focus on three main classes targeting the RNA-dependent RNA polymerase, the two viral proteases 3CL pro and PL pro and viral entry pathways, respectively.

CoVs use a multisubunit complex for RNA replication and transcription. This machinery is formed by nonstructural proteins, such as nsp7, nsp8, and nsp12, produced by the cleavage of viral polyproteins. Among them, RdRp (nsp12) is the key element since it has a prominent role in catalyzing RNA synthesis assisted by nsp7 and nsp8 that act as cofactors. 51, 52 Comparing the different coronaviral RdRp structures, they share a certain structural conservation. In particular, SARS-CoV and SARS-CoV-2 show a remarkable sequence conservation (96%) with variations distant to the catalytic site highlighting the possibility to have broad-spectrum antivirals for different CoVs infections. 53 The main class of antiviral drugs that target RdRp is represented by nucleoside analogues.

At present, both FDA-approved and experimental nucleoside analogues are and have been tested in clinical trials, some of them showing promising results (R 1 and R 5 Table 1 ). [54] [55] [56] [57] Ribavirin (R 3 ) is a broad-spectrum guanosine analogue active against several RNA viruses, approved for the treatment of HCV and RSV infections. 58, 59 Ribavirin showed a moderate inhibitory effect on the replication of human CoVs in vitro and contrasting results in animal models of MERS-CoV and SARS-CoV infections. 54, 60, 61 In particular, ribavirin administration in a mouse model of SARS-CoV infection caused an increase in viral load and a prolonged viral replication, while, in association with interferon-alpha2b, an improvement of the clinical outcome in a nonhuman primate model (rhesus macaques) of MERS-CoV infection. 62, 63 Ribavirin has been widely used during SARS and MERS outbreaks, however, clinical data are inconclusive and contradictory. [64] [65] [66] [67] [68] For example, a retrospective multicenter non-randomized study reported a remarkable (93.5%) 21-day survival in SARS patients treated with ribavirin, however, due to the retrospectivity of this study and the absence of a control group, it is impossible to understand if the treatment regimen had a real beneficial effect on the clinical outcome. 64 In this context, another clinical study highlighted the beneficial effects of the use of ribavirin in combination with corticosteroids, with resolution of symptoms and radiographic improvement in the majority of the patients. 65 In contrast to this, there are several clinical studies in which the use of ribavirin, alone or in combination with corticosteroids or interferon, did not show any beneficial effects in patients with TA B L E 1 List of FDA-approved and preclinical agents effective in vitro against SARS-CoV, MERS-CoV, and SARS-CoV-2 infections. The half-maximal effective concentration (EC 50 ) is referred to the inhibition of viral replication or induced cytopathic effect. An alphanumerical reference has been introduced for elucidated or hypothesized target. C refers to 3CL pro , E to viral entry pathways, P to PL pro , R to RdRp and T to translation SARS or MERS and, in some cases, caused a worsening of the clinical situation. [66] [67] [68] Moreover, most clinical studies report the frequent occurrence of adverse effects associated with the administration of high-dose ribavirin such as hemolytic anemia, hypomagnesemia, hypocalcemia, and hepatoxicity. 67, 69 In this regard, in a reasonably sized clinical study involving 110 SARS patients treated with ribavirin, hemolytic anemia occurred in 61% of patients and 28% of these patients required blood transfusion. 69 In conclusion, the contrasting clinical data and ribavirin hematologic and liver toxicity represent limiting factors for its clinical use in CoVs infections.

Recently, an experimental nucleoside analogue, remdesivir (R 1 )

has been recognized as a potential broad-spectrum antiviral drug against CoVs infections. It is an adenosine analogue prodrug with broad-spectrum activity against several RNA viruses such as filoviruses, coronaviruses, and paramyxoviruses. 55 Positive clinical data emerged also from a large size randomized trial involving 1063 hospitalized patients with Covid-19 reporting a significative reduction in recovery time for patients treated with remdesivir compared to the placebo group. 74 Although more clinical data are required, due to its therapeutic efficacy and safety, remdesivir seems to be one of the most promising candidate for the treatment of CoVs infections.

In addition to remdesivir, other two investigational nucleoside 57 Moreover, an orally bioavailable prodrug has been developed in order to improve its pharmacokinetic properties. 56 

The two main coronaviral proteases, 3CL pro and PL pro , represent potential drug target since they are essential for viral replication and seem to contribute to viral infection. (Table 2 ). However, most of them have not been tested in vitro and in animal models.

SARS-CoV PL pro can be targeted by different types of protease inhibitors like zinc ion, zinc derivatives, thiopurine analogues, and naphthalene inhibitors. [85] [86] [87] Thiopurine analogues, such as 6-thioguanine and 6-mercaptopurine, have shown to inhibit also the deubiquitinating and proteolytic activity of MERS-CoV PL pro . 88 Numerous inhibitors have been identified for 3CL pro , they can be classified into two groups: peptidomimetic inhibitors and small molecule inhibitors.

Peptidomimetic inhibitors generally are constituted by a peptide skeleton similar to the natural substrate and warhead groups such as aldehydes, nitriles, ketones, Michael acceptors, etc. 89 In this regard, a noteworthy example of broad-spectrum peptidomimetic inhibitor has been recently reported: it is a-ketoamide inhibitor (C 9 ) derived from a peptidomimetic inhibitor active against the 3CL pro of betacoronaviruses, alphacoronaviruses, and enteroviruses. 90, 91 Specifically, in order to improve the pharmacokinetic profile, a pyridone ring was introduced to hide the amide bond and the cinnamoyl group was replaced by a Boc group.

Interestingly, the new designed compound (C 9 ) showed po- In addition to disulfiram, in a recent study, five compounds, approved or pharmacologically active, including Ebselen, Tideglusib, Carmofur, Shikonin, and PX-12 showed inhibitory activity against TA B L E 2 List of FDA-approved and preclinical agents active against the two viral proteases, 3CL pro and PL pro , of SARS-CoV, MERS-CoV, and SARS-CoV-2. Data summarized are the results from in vitro experiments using recombinant proteins as well as structure-assisted drug design and virtual screening. The inhibitory activity is expressed as IC 50 and referred to the proteolytic or deubiquitinating activity Naphtalene-based inhibitors (GRL0617) PL pro 0.6 [191] Benzotriazole-based inhibitors (XP-59) 3CL pro 0.1 [92] Zinc ion PL pro 1.3 [87] Zinc conjugates (N-ethyl-N-phenyldithio carbamic acid) PL pro 3.3 [87] Isatin derivatives(compound 8k 1 ) 3CL pro 1.04 5.8 [93] Neuraminidase inhibitors derivatives (compound 3i) 3CL pro 7.4 [94] Pyrazolone derivatives (compound 2t) 3CL pro 6.8 [95] Pyrithiobac derivatives (compound 6-4) 3CL pro 3.30 [96] Triazole-based inhibitors (compound 14d) 3CL pro 8.95 [97] Diphenyl sulfone-based inhibitors (compound 3) 3CL pro 0.3 [98] Pyrimidine derivatives (compound 6m) 3CL pro 6.1 [99] Chloropyridinil ester-derived inhibitors (compound 10) 3CL pro 0.003 [100] Nitrile-based peptidomimetic inhibitors (Cbz-AVLQ-CN) 3CL pro 4.6 [200] Aldehyde-based peptidomimetic inhibitors (TG-0204998) 3CL pro 0.038 [201] a-ketoamide inhibitors (compound 11s) Positive clinical data emerge also from a multicenter retrospective clinical study that, however, highlights the beneficial effect of this therapy only if used at the early stages of the infection and not as rescue therapy. 115 The ineffectiveness of the use of lopinavir/ ritonavir as rescue therapy has been also reported in a reasonably 

Among the structural proteins, the spike glycoprotein is particularly interesting since it mediates host-cell entry of CoVs representing an important drug target site. It is a type I transmembrane protein that shows the same structural organization for several CoVs: a N-terminal domain, called S1, containing the receptor binding-domain (RBD), responsible for cellular receptor binding, and a C-terminal domain, called S2, that mediates viral fusion process. 119 Comparing the different structures, SARS-CoV and SARS-CoV-2 share a moderate sequence identity (76%) with a higher similarity (89.8%) in their S2 subunit. 53, 120 Remarkably, a highly conserved region named the heptad repeat (HR) is located in the S2 domain and represents an appealing target for the development of broad-spectrum antiviral drugs. In this regard, in a recent study, a potent broad-spectrum peptidic entry inhibitor named EK1 (E 17 ) that targets the HR domain was developed. Based on these findings, FDA-approved drugs that exhibit cathepsins inhibitory activity such as antimicrobials (E 5 -E 8 ), antimalarials (E 9 -E 11 ), and antidepressants (E 1 -E 4 ) were proven to inhibit viral entry and infection in cell culture. 83, [131] [132] [133] [134] [135] Among them, we find two much-debated drugs that have attracted most of the attention in Covid-19 pandemic: chloroquine (E 9 ) and its less toxic derivative hydroxychloroquine (E 10 ).

They are well-known antimalarial agents used also for the treatment of autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis. In addition to these pharmacological effects, chloroquine shows also broad-spectrum antiviral activity against a wide range of viruses such as orthomyxoviruses, retroviruses, and coronaviruses. 136 In addition to these strategies, another interesting approach to inhibit viral entry has recently emerged and regards the use of cellular receptors in order to block and prevent viral host uptake. In the light of this, an alternative and safer therapeutic approach to plasma therapy is represented by the passive administration of monoclonal antibodies. In the last years, this strategy has attracted growing interest since it shows the potential to be effective in both prophylaxis and treatment of CoVs infections without leading to immune-mediated side reactions associated with plasma therapy. [160] [161] [162] All the developed anti-CoVs monoclonal antibodies to date target the spike glycoprotein and, depending on the targeted domain, In this regard, a highly conserved epitope in the RBD of Sarbecovirus genus was found becoming an attractive target for the design of broad-spectrum monoclonal antibodies and vaccines. Although the RBD is the main target for anti-CoVs monoclonal antibodies, recently, the N-terminal domain of the S1 has emerged as critical epitope for some potent human monoclonal antibodies, such as 4A8 and 7D10. 172, 173 In the light of this, monoclonal antibodies can be considered potential candidates for prophylaxis and treatment of viral infections especially when no specific vaccines are available. However, the use of monoclonal antibodies for the treatment of viral infections has some additional drawbacks such as high cost of production, and, on. 176, 180 In the light of this, monoclonal antibodies efficacy, safety, and pharmacokinetic profiles should be further investigated in animal models and clinical studies are clearly needed in order to evaluate their real prophylactic/therapeutic efficacy.

Coronaviruses represent global health threat since they caused serious epidemics and pandemics leading to global health emergencies in the last decade. 

Camilla Servidio thanks the project POR Calabria FESR/FSE 2014-2020.

None of the authors has any potential conflicts of interest

Key protein targets and ligands in this article are hyperlinked to corresponding entries in http://www.guide topha rmaco logy. 

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Francesco Stellacci https://orcid.org/0000-0003-4635-6080

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MERS-CoV spike protein: a key target for antivirals

Neutralizing antibodies against SARS-CoV-2 and other human coronaviruses

Potent neutralization of MERS-CoV by human neutralizing monoclonal antibodies to the viral spike glycoprotein

Potent cross-reactive neutralization of SARS coronavirus isolates by human monoclonal antibodies

Prophylactic and postexposure efficacy of a potent human monoclonal antibody against MERS coronavirus

Cross-neutralization of SARS-CoV-2 by a human monoclonal SARS-CoV antibody

Broad neutralization of SARS-related viruses by human monoclonal antibodies

A human monoclonal antibody blocking SARS-CoV-2 infection

A highly conserved cryptic epitope in the receptor binding domains of SARS-CoV-2 and SARS-CoV

Human neutralizing antibodies elicited by SARS-CoV-2 infection

A neutralizing human antibody binds to the N-terminal domain of the Spike protein of SARS-CoV-2

Structural definition of a neutralization epitope on the N-terminal domain of MERS-CoV spike glycoprotein

A perspective on potential antibody-dependent enhancement of SARS-CoV-2

Antibodydependent enhancement and SARS-CoV-2 vaccines and therapies

Antibody-dependent enhancement of SARS coronavirus infection and its role in the pathogenesis of SARS

Active replication of Middle East respiratory syndrome coronavirus and aberrant induction of inflammatory cytokines and chemokines in human macrophages: implications for pathogenesis

replication competence, and innate immune responses of the coronavirus SARS-CoV-2 in human respiratory tract and conjunctiva: an analysis in ex-vivo and in-vitro cultures

Immunodominant SARS coronavirus epitopes in humans elicited both enhancing and neutralizing effects on infection in non-human primates

Implications of antibody-dependent enhancement of infection for SARS-CoV-2 countermeasures

The IUPHAR/BPS Guide to PHARMACOLOGY in 2018: updates and expansion to encompass the new guide to IMMUNOPHARMACOLOGY

The concise guide to pharmacology 2019/20: enzymes

Identification of nafamostat as a potent inhibitor of Middle East respiratory syndrome coronavirus S protein-mediated membrane fusion using the splitprotein-based cell-cell fusion assay

Protease inhibitors targeting coronavirus and filovirus entry

A novel peptide with potent and broad-spectrum antiviral activities against multiple respiratory viruses

Testing of Middle East respiratory syndrome coronavirus replication inhibitors for the ability to block viral entry

Cinanserin is an inhibitor of the 3C-like proteinase of severe acute respiratory syndrome coronavirus and strongly reduces virus replication in vitro

Synthesis, crystal structure, structure− activity relationships, and antiviral activity of a potent SARS coronavirus 3CL protease inhibitor

Structureguided design of potent and permeable inhibitors of MERS coronavirus 3CL protease that utilize a piperidine moiety as a novel design element

Yeast based small molecule screen for inhibitors of SARS-CoV

A noncovalent class of papain-like protease/deubiquitinase inhibitors blocks SARS virus replication

Small molecules targeting severe acute respiratory syndrome human coronavirus

Discovery of the FDA-approved drugs bexarotene, cetilistat, diiodohydroxyquinoline, and abiraterone as potential COVID-19 treatments with a robust two-tier screening system

The SARS-coronavirus-host interactome: identification of cyclophilins as target for pan-coronavirus inhibitors

Alisporivir inhibits MERS-and SARS-coronavirus replication in cell culture, but not SARS-coronavirus infection in a mouse model

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

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

Bismuth complexes inhibit the SARS coronavirus

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

Design, synthesis and crystallographic analysis of nitrile-based broad-spectrum peptidomimetic inhibitors for coronavirus 3C-like proteases

Structural basis of inhibition specificities of 3C and 3C-like proteases by zinc-coordinating and peptidomimetic compounds

Identification and evaluation of potent Middle East respiratory syndrome coronavirus (MERS-CoV) 3CLPro inhibitors

Dipeptidyl peptidase 4 distribution in the human respiratory tract: implications for the Middle East respiratory syndrome

Structure of HIV-1 protease in complex with potent inhibitor KNI-272 determined by high-resolution X-ray and neutron crystallography

Therapeutic approaches against coronaviruses acute respiratory syndrome