Computational modeling and inhibition of SARS-COV-2 Papain-like protease enzyme:A potential therapeutic approach for COVID-19

This study aims to investigate the potential impact of inhibitors targeting the papain-like protease(PLpro)of SARS-CoV-2 on viral replication and the host immune response.A mathematical model was developed to simulate the interaction among susceptible cells,infected cells,PLpro,and immune cells,incorporating data on PLpro inhibition.Through numerical simulations using MATLAB,the model parameters were estimated based on available statistical data.The results indicate that strategically positioned inhibitors could impede the virus’s access to host cellular machinery,thereby enhancing the immune response and gradually reducing susceptible and infected cells over time.The dynamics of the viral enzyme PLpro showed reduced activity with the introduction of the inhibitor,leading to a decline in viral replication.Moreover,the immune cell population exhibited functional recovery as the inhibitor suppressed PLpro activity.These findings suggest that inhibitors targeting PLpro may serve as therapeutic interventions against SARS-CoV-2 by inhibiting viral replication and bolstering the immune response.

High-throughput screening identifies established drugs as SARS-CoV-2 PLpro inhibitors

A new coronavirus(SARS-CoV-2)has been identified as the etiologic agent for the COVID-19 outbreak.Currently,effective treatment options remain very limited for this disease;therefore,there is an urgent need to identify new anti-COVID-19 agents.In this study,we screened over 6,000 compounds that included approved drugs,drug candidates in clinical trials,and pharmacologically active compounds to identify leads that target the SARS-CoV-2 papain-like protease(PLpro).Together with main protease(Mpro),PLpro is responsible for processing the viral replicase polyprotein into functional units.There-fore,it is an attractive target for antiviral drug develop-ment.Here we discovered four compounds,YM155,cryptotanshinone,tanshinone I and GRL0617 that inhibit SARS-CoV-2 PLpro with IC50 values ranging from 1.39 to 5.63 pmol/L.These compounds also exhibit strong antiviral activities in cell-based assays.YM155,an anti-cancer drug candidate in clinical trials,has the most potent antiviral activity with an EC50 value of 170 nmol/L.In addition,we have determined the crystal structures of this enzyme and its complex with YM155,revealing a unique binding mode.YM155 simultaneously targets three"hot"spots on PLpro,including the substrate-binding pocket,the interferon stimulating gene product 15(ISG15)binding site and zinc finger motif.Our results demonstrate the efficacy of this screening and repur-posing strategy,which has led to the discovery of new drug leads with clinical potential for COVID-19 treatments.