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Design, Synthesis, and Unprecedented Interactions of Covalent Dipeptide-Based Inhibitors of SARS-CoV-2 Main Protease and Its Variants Displaying Potent Antiviral Activity

Authors :
Flury, Philipp
Krüger, Nadine
Sylvester, Katharina
Breidenbach, Julian
Al Hamwi, Ghazl
Qiao, Jingxin
Chen, Yan
Rocha, Cheila
Serafim, Mateus Sá Magalhães
Barbosa da Silva, Elany
Pöhlmann, Stefan
Poso, Antti
Kronenberger, Thales
Rox, Katharina
O’Donoghue, Anthony J.
Yang, Shengyong
Sträter, Norbert
Gütschow, Michael
Laufer, Stefan A.
Müller, Christa E.
Pillaiyar, Thanigaimalai
Source :
Journal of Medicinal Chemistry; 20250101, Issue: Preprints
Publication Year :
2025

Abstract

The main protease (Mpro) of SARS-CoV-2 is a key drug target for the development of antiviral therapeutics. Here, we designed and synthesized a series of small-molecule peptidomimetics with various cysteine-reactive electrophiles. Several compounds were identified as potent SARS-CoV-2 Mproinhibitors, including compounds 8n(IC50= 0.0752 μM), 8p(IC50= 0.0887 μM), 8r(IC50= 0.0199 μM), 10a(IC50= 0.0376 μM), 10c(IC50= 0.0177 μM), and 10f(IC50= 0.0130 μM). Most of them additionally inhibited cathepsin L and were also active against SARS-CoV-1 and MERS-CoV Mpro. In Calu-3 cells, several inhibitors, including 8r, 10a, and 10c, displayed high antiviral activity in the nanomolar range without showing cellular toxicity. The cocrystal structure of SARS-CoV-2 Mproin complex with 8prevealed covalent binding to the enzyme’s catalytic residue Cys145 and showed specific, unprecedented interactions within the substrate binding pocket. Compounds 10cand especially 8nwere effective against a panel of naturally occurring nirmatrelvir-resistant mutants, particularly E166V, and showed metabolic stability and additional favorable pharmacokinetic properties, making it a suitable candidate for further preclinical development.

Details

Language :
English
ISSN :
00222623 and 15204804
Issue :
Preprints
Database :
Supplemental Index
Journal :
Journal of Medicinal Chemistry
Publication Type :
Periodical
Accession number :
ejs68628948
Full Text :
https://doi.org/10.1021/acs.jmedchem.4c02254