%0 Journal Article
%A Kuzikov, Maria
%A Costanzi, Elisa
%A Reinshagen, Jeanette
%A Esposito, Francesca
%A Vangeel, Laura
%A Wolf, Markus
%A Ellinger, Bernhard
%A Claussen, Carsten
%A Geisslinger, Gerd
%A Corona, Angela
%A Iaconis, Daniela
%A Talarico, Carmine
%A Manelfi, Candida
%A Cannalire, Rolando
%A Rossetti, Giulia
%A Gossen, Jonas
%A Albani, Simone
%A Musiani, Francesco
%A Herzog, Katja
%A Ye, Yang
%A Giabbai, Barbara
%A Demitri, Nicola
%A Jochmans, Dirk
%A Jonghe, Steven De
%A Rymenants, Jasper
%A Summa, Vincenzo
%A Tramontano, Enzo
%A Beccari, Andrea R.
%A Leyssen, Pieter
%A Storici, Paola
%A Neyts, Johan
%A Gribbon, Philip
%A Zaliani, Andrea
%T Identification of Inhibitors of SARS-CoV-2 3CL-Pro Enzymatic Activity Using a Small Molecule in Vitro Repurposing Screen
%J ACS pharmacology & translational science
%V 4
%N 3
%@ 2575-9108
%C Washington, DC
%I ACS Publications
%M FZJ-2021-06125
%P 1096 - 1110
%D 2021
%X 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, SARS-CoV-2 main protease (3CL-Pro), also termed M-Pro, is an attractive drug target as it plays a central role in viral replication by processing the viral polyproteins pp1a and pp1ab at multiple distinct cleavage sites. We here report the results of a repurposing program involving 8.7 K compounds containing marketed drugs, clinical and preclinical candidates, and small molecules regarded as safe in humans. We confirmed previously reported inhibitors of 3CL-Pro and have identified 62 additional compounds with IC50 values below 1 μM and profiled their selectivity toward chymotrypsin and 3CL-Pro from the Middle East respiratory syndrome virus. A subset of eight inhibitors showed anticytopathic effect in a Vero-E6 cell line, and the compounds thioguanosine and MG-132 were analyzed for their predicted binding characteristics to SARS-CoV-2 3CL-Pro. The X-ray crystal structure of the complex of myricetin and SARS-Cov-2 3CL-Pro was solved at a resolution of 1.77 Å, showing that myricetin is covalently bound to the catalytic Cys145 and therefore inhibiting its enzymatic activity.
%F PUB:(DE-HGF)16
%9 Journal Article
%U <Go to ISI:>//WOS:000662229400007
%R 10.1021/acsptsci.0c00216
%U https://juser.fz-juelich.de/record/904555