Beyond the vaccines: a glance at the small molecule and peptide-based anti-COVID19 arsenal

Abstract

Unprecedented efforts of the researchers have been witnessed in the recent past towards the development of vaccine platforms for the control of the COVID-19 pandemic. Albeit, vaccination stands as a practical strategy to prevent SARS-CoV-2 infection, supplementing the anti-COVID19 arsenal with therapeutic options such as small molecules/peptides and antibodies is being conceived as a prudent strategy to tackle the emerging SARS-CoV-2 variants. Noteworthy to mention that collective efforts from numerous teams have led to the generation of a voluminous library composed of chemically and mechanistically diverse small molecules as anti-COVID19 scaffolds. This review article presents an overview of medicinal chemistry campaigns and drug repurposing programs that culminated in the identification of a plethora of small molecule-based anti-COVID19 drugs mediating their antiviral effects through inhibition of proteases, S protein, RdRp, ACE2, TMPRSS2, cathepsin and other targets. In light of the evidence ascertaining the potential of small molecule drugs to approach conserved proteins required for the viral replication of all coronaviruses, accelerated FDA approvals are anticipated for small molecules for the treatment of COVID19 shortly. Though the recent attempts invested in this direction in pursuit of enrichment of the anti-COVID-19 armoury (chemical tools) are praiseworthy, some strategies need to be implemented to extract conclusive benefits of the recently reported small molecule viz. (i) detailed preclinical investigation of the generated anti-COVID19 scaffolds (ii) in-vitro profiling of the inhibitors against the emerging SARS-CoV-2 variants (iii) development of assays enabling rapid screening of the libraries of anti-COVID19 scaffold (iv) leveraging the applications of machine learning based predictive models to expedite the anti-COVID19 drug discovery campaign (v) design of antibody–drug conjugates.

Targeting SARS-CoV-2 and host cell receptor interactions

“…Besides interfering with virus-receptor interactions, repurposed drugs that block spike-mediated cell fusion ( Mediouni et al, 2022 ; Chen et al, 2020 ; Riva et al, 2020 ) or enzymatic activities of ACE2 (MLN-4760), TMPRSS2 (Camostat mesylate and Nafamostat), cathepsins (Eicoplanin, calpain inhibitor II, XII), furin (reviewed in Nepali et al, 2022 ) have been described. Indeed, a few repurposed drugs have entered the clinic for treatment of COVID-19 and they include Niclosamide (oral or inhaled formulation; phase III) which acts as a protonophore to interfere with viral entry and egress ( Singh et al, 2022 ), Nafamostat ( Zhuravel, 2021 ; phase II/III), Camostat (phase I/II), Amiodarone and Verapamil (inhibit endosomal processing ( Stadler et al, 2008 ; phase II/III), Umifenovir (Arbidol; targets S-protein and prevents viral fusion; Nojomi et al, 2020 ; phase III/IV).…”

Studies on the selectivity of the SARS-CoV-2 papain-like protease reveal the importance of the P2′ proline of the viral polyprotein

“…[4][5][6] However, clinical use of PL pro inhibitors has not yet been approved. 3,7,8 Although M pro and PL pro are both nucleophilic cysteine proteases, they differ in their structures, catalytic mechanisms, and substrate selectivities. 7 M pro is predominantly homodimeric and employs an active site Cys-His dyad to catalyze hydrolysis of the SARS-CoV-2 polyproteins at 11 sites, which have [P4:A/V/P/T]-[P3:X]-[P2:L/F/V]-[P1:Q]|[P1 0 :S/A/N] motifs, where ''|'' denotes the scissile amide bond and X corresponds to any proteinogenic amino acid.…”

Structure-Based Design of Potent Iminosugar Inhibitors of Endoplasmic Reticulum α-Glucosidase I with Anti-SARS-CoV-2 Activity

“…Glucose-mimicking compounds that competitively inhibit ER α-GluI and α-GluII have demonstrated in vitro and, in some cases, in vivo antiviral efficacy against a wide range of enveloped viruses, notably influenza, dengue, hepatitis C, Ebola, and SARS-CoV-2. ,− The best-studied inhibitors of α-GluI and α-GluII are N -substituted derivatives of the iminosugar 1-deoxynojirimycin (1-DNJ), − in which a nitrogen atom has replaced oxygen in the sugar ring. Recently, a single dose of N -9′-methoxynonyl 1-deoxynojirimycin (UV-4) was shown to prevent death of mice infected with lethal doses of influenza or dengue virus, even when treatment was begun as late as 48 h post-infection .…”