Journal Article

PUBDB-2025-00399

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Design, Synthesis, and Unprecedented Interactions of Covalent Dipeptide-Based Inhibitors of SARS-CoV-2 Main Protease and Its Variants Displaying Potent Antiviral Activity

Flury, P. ; Krüger, N. ; Sylvester, K. ; Breidenbach, J. ; Al Hamwi, G. ; Qiao, J. ; Chen, Y. ; Rocha, C. ; Serafim, M. S. M. ; Barbosa da Silva, E. ; Pöhlmann, S. ; Poso, A. ; Kronenberger, T. ; Rox, K. ; O’Donoghue, A. J. ; Yang, S. ; Straeter, N.Extern* ; Gütschow, M. ; Laufer, S. A. ; Müller, C. E. ; Pillaiyar, T. (Corresponding author)

2025
ACS Washington, DC

This record in other databases:        

Please use a persistent id in citations: doi:10.1021/acs.jmedchem.4c02254

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 Mpro inhibitors, 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 Mpro in complex with 8p revealed covalent binding to the enzyme’s catalytic residue Cys145 and showed specific, unprecedented interactions within the substrate binding pocket. Compounds 10c and especially 8n were 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.

Note: Waiting for fulltext

---

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)

Appears in the scientific report 2025

---

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

---