Identification of Inhibitors of SARS-CoV-2 3CL-Pro Enzymatic Activity Using a Small Molecule in Vitro Repurposing Screen

• DOI: 10.1021/acsptsci.0c00216
• Publication Date: 2021-03-11T21:43:30Z
• Authors: Maria Kuzikov; Elisa Costanzi; Jeanette Reinshagen; Francesca Esposito; Laura Vangeel; Markus Wolf; Bernhard Ellinger; Carsten Claussen; Gerd Geisslinger; Angela Corona; Daniela Iaconis; Carmine Talarico; Candida Manelfi; Rolando Cannalire; Giulia Rossetti; Jonas Gossen; Simone Albani; Francesco Musiani; Katja Herzog; Yang Ye; Barbara Giabbai; Nicola Demitri; Dirk Jochmans; Steven De Jonghe; Jasper Rymenants; Vincenzo Summa; Enzo Tramontano; Andrea R. Beccari; Pieter Leyssen; Paola Storici; Johan Neyts; Philip Gribbon; Andrea Zaliani
• Keywords: Drug repositioning; Vero cell; Repurposing

Compound repurposing is an important strategy for the identification of effective treatment options against SARS-CoV-2 infection and COVID-19 disease. In this regard, main protease (3CL-Pro), also termed M-Pro, attractive drug target as it plays a central role in viral replication by processing polyproteins pp1a pp1ab at multiple distinct cleavage sites. We here report results program involving 8.7 K compounds containing marketed drugs, clinical preclinical candidates, small molecules regarded safe humans. confirmed previously reported inhibitors 3CL-Pro have identified 62 additional with IC50 values below 1 μM profiled their selectivity toward chymotrypsin from Middle East respiratory syndrome virus. A subset eight showed anticytopathic effect Vero-E6 cell line, thioguanosine MG-132 were analyzed predicted binding characteristics to 3CL-Pro. The X-ray crystal structure complex myricetin SARS-Cov-2 was solved resolution 1.77 Å, showing that covalently bound catalytic Cys145 therefore inhibiting its enzymatic activity.