Journal Article

PUBDB-2024-06891

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Discovery and Crystallographic Studies of Nonpeptidic Piperazine Derivatives as Covalent SARS-CoV-2 Main Protease Inhibitors

Gao, S. ; Song, L. ; Claff, T. ; Woodson, M. ; Sylvester, K. ; Jing, L. ; Weiße, R. H. ; Cheng, Y. ; Straeter, N.Extern* ; Schäkel, L. ; Gütschow, M. ; Ye, B. ; Yang, M. ; Zhang, T. ; Kang, D. ; Toth, K. ; Tavis, J. ; Tollefson, A. E. ; Müller, C. E. (Corresponding author) ; Zhan, P. (Corresponding author) ; Liu, X. (Corresponding author)

2022
ACS Washington, DC

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Please use a persistent id in citations: doi:10.1021/acs.jmedchem.2c01716

Abstract: The spread of SARS-CoV-2 keeps threatening human life and health, and small-molecule antivirals are in demand. The main protease (Mpro) is an effective and highly conserved target for anti-SARS-CoV-2 drug design. Herein, we report the discovery of potent covalent non-peptide-derived Mpro inhibitors. A series of covalent compounds with a piperazine scaffold containing different warheads were designed and synthesized. Among them, GD-9 was identified as the most potent compound with a significant enzymatic inhibition of Mpro (IC50 = 0.18 μM) and good antiviral potency against SARS-CoV-2 (EC50 = 2.64 μM), similar to that of remdesivir (EC50 = 2.27 μM). Additionally, GD-9 presented favorable target selectivity for SARS-CoV-2 Mpro versus human cysteine proteases. The X-ray co-crystal structure confirmed our original design concept showing that GD-9 covalently binds to the active site of Mpro. Our nonpeptidic covalent inhibitors provide a basis for the future development of more efficient COVID-19 therapeutics.

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Contributing Institute(s):

1. EMBL-User (EMBL-User)

Research Program(s):

1. 6G3 - PETRA III (DESY) (POF4-6G3) (POF4-6G3)

Experiment(s):

1. PETRA Beamline P13 (PETRA III)
2. PETRA Beamline P14 (PETRA III)

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Chemical Reactions ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 5 ; Index Chemicus ; JCR ; Nationallizenz ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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