Characterization and Inhibition of the Main Protease of Severe Acute Respiratory Syndrome Coronavirus

Abstract

The main protease of SARS-associated coronavirus (SARS-CoV), also called 3C-like protease (3CL pro ), is vital for the viral replication. It cleaves the replicase polyproteins at 11 sites and is a promising drug target. Several groups of inhibitors have been identified through high-throughput screening and rational drug design. In addition to the pharmaceuti-cal applications, a mutant 3CL pro (T25G) with an expanded S1 space has been demonstrated to tolerate larger residues at P1 , facilitating the cleavage behind the recognition sequence. This review summarizes current developments in anti-SARS agents targeting 3CL pro and the application of the mutant protease as a tag-cleavage endopeptidase.

The Molecular Mechanism of Domain Swapping of the C-Terminal Domain of the SARS-Coronavirus Main Protease

“…Residues of M pro C also participate in the non-domain-swapping dimerization ( 15 , 17 ) of M pro . Previous mutation and drug binding studies have focused on both this non-domain-swapping dimerization interface and residues that are important for enzyme function ( 16 , 19 , 20 , 21 , 25 , 78 , 79 , 80 , 81 ). Using our simulations, we suggest that binding competent sites near the L1–L4 interaction region could be used to lock M pro C and, in turn, M pro into a non-domain-swapping monomer.…”

Biochemical screening for SARS-CoV-2 main protease inhibitors

“…M pro is thought to specifically cleave the viral polyprotein 1ab at 11 cleavage sites. The sequence recognized contains in most cases Leu-Gln-(Ser/Ala/Gly) with cleavage occurring after the Gln residue [ 5 – 7 ]. Although currently several promising therapeutic strategies against SARS-CoV-2 are in development [ 8 ], no established COVID-19 drug or vaccine exists.…”

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

“…Due to its vital role in replication, 3CL pro has been regarded as a validated drug target. Many inhibitors of SARS-CoV 3CL pro were discovered by high throughput screening and structure-based rational design as summarized in the review articles (Hilgenfeld and Peiris, 2013;Kumar et al, 2013;Kuo and Liang, 2015;Pillaiyar et al, 2016;Ramajayam et al, 2011;Tong, 2009;Zhao et al, 2013). After SARS-CoV infection subsided, Middle East respiratory syndrome CoV (MERS-CoV), has emerged in Saudi Arabia in 2012 and spread worldwide, killing 36% of the reported 1826 patients (http://www.who.int/mediacentre/factsheets/mers-cov/ en/).…”