Targeting SARS-CoV-2 M3CLpro by HCV NS3/4a Inhibitors: In Silico Modeling and In Vitro Screening

Abstract

Currently the entire human population is in the midst of a global pandemic caused by SARS-CoV-2 ( S evere A cute R espiratory S yndrome Co rona V irus 2). This highly pathogenic virus has to date caused >71 million infections and >1.6 million deaths in >180 countries. Several vaccines and drugs are being studied as possible treatments or prophylactics of this viral infection. M3CLpro (coronavirus main cysteine protease) is a promising drug target as it has a significant role in viral replication. Here we use the X-ray crystal structure of M3CLpro in complex with boceprevir to study the dynamic changes of the protease upon ligand binding. The binding free energy was calculated for water molecules at different locations of the binding site, and molecular dynamics (MD) simulations were carried out for the M3CLpro/boceprevir complex, to thoroughly understand the chemical environment of the binding site. Several HCV NS3/4a protease inhibitors were tested in vitro against M3CLpro. Specifically, asunaprevir, narlaprevir, paritaprevir, simeprevir, and telaprevir all showed inhibitory effects on M3CLpro. Molecular docking and MD simulations were then performed to investigate the effects of these ligands on M3CLpro and to provide insights into the chemical environment of the ligand binding site. Our findings and observations are offered to help guide the design of possible potent protease inhibitors and aid in coping with the COVID-19 pandemic.

A Review of the Current Landscape of SARS-CoV-2 Main Protease Inhibitors: Have We Hit the Bullseye Yet?

“…Boceprevir and telaprevir are approved protease inhibitors for treating hepatitis caused by the hepatitis C virus. Both compounds have been identified several times as covalent inhibitors of the SARS-CoV-2 M-pro [ 43 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 ]. New bicycloproline derivatives have been designed and synthesized from them both [ 59 ].…”

Xanthohumol Is a Potent Pan-Inhibitor of Coronaviruses Targeting Main Protease

“…Interestingly, many protease inhibitors were clinically used for HIV treatments [43], of which Lopinavir, Indinavir, and Darunavir have been repurposed to inhibit SARS-CoV-2 M pro [44]. The HCV NS3-4A protease drug, boceprevir, could inhibit SARS-CoV-2 replication by targeting M pro in our and other groups' independent studies [45,46]. To be noted, PRRSV belongs to Arteriviridae.…”

Antiviral Activity of Metabolites from Peruvian Plants against SARS-CoV-2: An In Silico Approach

“…To date, there is no drug specifically formulated for the treatment of Covid-19 and approved by the FDA. Therefore, specific candidates were repurposed from their actual use among the best results, such as the antiretrovirals boceprevir, asunaprevir, narlaprevir, paritaprevir, and telaprevir, used for the hepatitis C and Lopinavir for HIV treatments, whose effect on the protein Mpro are still being evaluated [72,73]. In our study, when we compared the inhibitory effect of Lopinavir to Rutin, we observed a similar positive effect between both compounds within the Mpro pocket, confirming the potential of Rutin against SARS-CoV-2 Mpro.…”