Discovery of new PLpro inhibitors against SARS-CoV-2

There is an urgent need of effective drugs for the treatment of the SARS-CoV-2 infection. Remdesivir (Veklury), a nucleotide analogue, is the only drug that was approved by FDA on 22-Oct-2020 for certain COVID-19 patients. We performed virtual screening studies of a proprietary compound library of >6000 molecules against conserved SARS-CoV-2 enzymes, namely papain-like protease (PLpro), 3C-like proteinase (3CLpro) e RNA-dependent RNA polymerase (RdRp). In these preliminary docking studies, we identified compounds with EC50 values in low micromolar range of concentration against SARS-CoV-2 mucIMB and mucIMB-CB (alpha variant) strains in Vero B6 cells. In particular, compound RS2523 inhibited the SARS-CoV-2 PLpro with IC50 = 27 microM and the SARS-HCoV-OC43 strain withIC50 = 4.3 microM. Compound RS2523 was selected as a lead compound for optimization studies.