March 3, 2026

Discovery of new PLpro inhibitors against SARS-CoV-2

Key Points

New compounds show effective inhibition of SARS-CoV-2 PLpro, suggesting promising treatment options.
In preliminary studies, compound RS2523 demonstrated an IC50 of 27 microM against SARS-CoV-2 and 4.3 microM against another strain.
Virtual screening was performed using a library of over 6000 molecules against key SARS-CoV-2 enzymes.
The findings indicate potential for further optimization of RS2523 as a lead compound for COVID-19 therapy.

Abstract

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.

Discovery of new PLpro inhibitors against SARS-CoV-2

Key Points

Abstract

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