Journal Article

FZJ-2021-06125

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Identification of Inhibitors of SARS-CoV-2 3CL-Pro Enzymatic Activity Using a Small Molecule in Vitro Repurposing Screen

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

2021
ACS Publications Washington, DC

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Please use a persistent id in citations: http://hdl.handle.net/2128/30615  doi:10.1021/acsptsci.0c00216

Abstract: 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.

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Contributing Institute(s):

1. Computational Biomedicine (IAS-5)
2. Computational Biomedicine (INM-9)
3. Jülich Supercomputing Center (JSC)

Research Program(s):

1. 5241 - Molecular Information Processing in Cellular Systems (POF4-524) (POF4-524)
2. 5111 - Domain-Specific Simulation & Data Life Cycle Labs (SDLs) and Research Groups (POF4-511) (POF4-511)

Appears in the scientific report 2021

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Database coverage:
; ; ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Emerging Sources Citation Index ; IF >= 5 ; JCR ; PubMed Central ; PubMed Central ; SCOPUS ; Web of Science Core Collection

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