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

: Kuzikov, M.; Costanzi, E.; Reinshagen, J.; Esposito, F.; Vangeel, L.; Wolf, M.; Ellinger, B.; Claussen, C.; Geisslinger, G.; Corona, A.; Iaconis, D.; Talarico, C.; Manelfi, C.; Cannalire, R.; Rossetti, G.; Gossen, J.; Albani, S.; Musiani, F.; Herzog, K.; Ye, Y.; Giabbai, B.; Demitri, N.; Jochmans, D.; Jonghe, S.D.; Rymenants, J.; Summa, V.; Tramontano, E.; Beccari, A.R.; Leyssen, P.; Storici, P.; Neyts, J.; Gribbon, P.; Zaliani, A.


ACS pharmacology & translational science 4 (2021), Nr.3, S.1096-1110
ISSN: 2575-9108
Fraunhofer ITMP ()

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.