Scheme 1 gives an overview of synthetic routes for the synthesis of inhibitors used for our SAR studies.Ĭompounds used for SAR. Thus, the information obtained in this study may form the basis for designing pan-(beta)coronavirus-PL pro inhibitors. Herein we report SARs for a series of rationally designed competitive, noncovalent, nonpeptidic active site-directed SARS-CoV PL pro inhibitors which, most likely, also apply to SARS-CoV-2 PL pro, as supported by virus inhibition data in cell culture and IC 50 values of a representative set of inhibitors on isolated SARS-CoV-2 PL pro in an enzyme-activity assay. Those different amino acids, T275/K274 and V301/I300 (labeled as SARS-CoV/SARS-CoV-2 PL pro) orient their side-chains away from the binding site not influencing direct protein-ligand interactions. In accordance with recent reports, 17, 18 our sequence and structural alignments revealed that the SARS-CoV-2 PL pro shares a high sequence identity and similar fold with its SARS-CoV homolog (sequence identity 82 %, similarity 90 %, C α-RMSD 1.8 Å, SARS-CoV PL pro PDB-ID 3E9S, SARS-CoV-2 PL pro PDB-ID 6WUU 19), especially in the binding site of the inhibitors reported herein, where only two amino acids differ. 16 The protease cleaves three sites with a LXGG↓ signature sequence in the N-proximal regions of pp1a and pp1ab (namely nsp1↓nsp2↓nsp3↓nsp4). PL pro is a cysteine protease with a classical Cys-His-Asp catalytic triad (Cys112, His273, Asp287) and a precatalytically deprotonated thiolate that acts as the nucleophile for proteolysis. 11, 13 Due to their key role in the production of active RTCs, coronavirus proteases are considered as promising drug targets. 12 The vast majority if these nsps is involved in the formation of membrane-anchored multi-subunit protein complexes that are referred to as coronavirus replication-transcription complexes (RTCs) which replicate the viral genome RNA and produce an extensive set of subgenomic mRNAs, the latter encoding viral structural and several accessory proteins. ![]() Upon cleavage, they release a total of 16 nonstructural proteins (nsp 1 to 16) from pp1a and pp1ab. 11 In SARS-like CoVs, pp1a and pp1ab are processed by two proteases, namely the coronavirus main protease (M pro, also called 3 C-like protease, 3CL pro) and papain-like protease (PL pro). Like many other positive-strand RNA viruses, CoVs express large polyproteins (called pp1a and pp1ab) that are processed by viral proteases at multiple sites. Inhibitors of viral proteases are highly effective drugs and are widely used in clinical practice, for example, in the treatment of HIV/AIDS and hepatitis C infections. In this context, viral proteases have been identified as promising targets for inhibiting the replication of viruses of diverse families, such as Coronaviridae, Flaviviridae, Retroviridae, and Picornaviridae. 10 Therefore, an improved understanding of structure-activity relationships (SAR) of inhibitors targeting critical steps in viral replication is of utmost importance and expected to facilitate drug development. To date, no causative treatment options for SARS, COVID-19 and MERS 9 have been approved. Genetically, the two viruses are very closely related and are members of the same coronavirus species called Severe acute respiratory syndrome-related coronavirus (subgenus Sarbecovirus, genus Betacoronavirus). The viruses responsible for the SARS outbreak in 2002/2003 and the ongoing COVID-19 pandemic are called SARS coronavirus (SARS-CoV) and SARS coronavirus 2 (SARS-CoV-2), respectively. Given the remarkable zoonotic potential of these viruses and the major impact of infections caused by these viruses on human health and the global economy, there is an urgent need to develop broadly acting antivirals that, ideally, should be effective against previously known and newly emerging coronaviruses. 1- 7 There is strong evidence that all these newly emerging coronaviruses have their natural reservoir in animals. ![]() Within the past two decades, members of the genus Betacoronavirus have caused three major outbreaks of severe respiratory disease in humans, including SARS (severe acute respiratory syndrome), MERS (Middle East respiratory syndrome), and coronavirus disease 19 (COVID-19).
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