Journal Article

PUBDB-2024-05680

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Macrocyclic Azapeptide Nitriles: Structure-Based Discovery of Potent SARS-CoV-2 Main Protease Inhibitors as Antiviral Drugs

Breidenbach, J. ; Voget, R. ; Si, Y. ; Hingst, A. ; Claff, T. ; Sylvester, K. ; Wolf, V. ; Krasniqi, V. ; Useini, A.Extern*EMBL* ; Straeter, N.Extern* ; Ogura, Y. ; Kawaguchi, A. ; Müller, C. E. ; Gütschow, M. (Corresponding author)

2024
ACS Washington, DC

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Please use a persistent id in citations: doi:10.1021/acs.jmedchem.4c00053

Abstract: Given the crucial role of the main protease (Mpro) in the replication cycle of SARS-CoV-2, this viral cysteine protease constitutes a high-profile drug target. We investigated peptidomimetic azapeptide nitriles as auspicious, irreversibly acting inhibitors of Mpro. Our systematic approach combined an Mpro active-site scanning by combinatorially assembled azanitriles with structure-based design. Encouraged by the bioactive conformation of open-chain inhibitors, we conceptualized the novel chemotype of macrocyclic azanitriles whose binding mode was elucidated by cocrystallization. This strategy provided a favorable entropic contribution to target binding and resulted in the development of the extraordinarily potent Mpro inhibitor 84 with an IC50 value of 3.23 nM and a second-order rate constant of inactivation, kinac/Ki, of 448,000 M–1s–1. The open-chain Mpro inhibitor 58, along with the macrocyclic compounds 83 and 84, a broad-spectrum anticoronaviral agent, demonstrated the highest antiviral activity with EC50 values in the single-digit micromolar range. Our findings are expected to promote the future development of peptidomimetic Mpro inhibitors as anti-SARS-CoV-2 agents.

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Contributing Institute(s):

1. EMBL-User (EMBL-User)

Research Program(s):

1. 6G3 - PETRA III (DESY) (POF4-6G3) (POF4-6G3)
2. GRK 2873 - GRK 2873: Werkzeuge und Wirkstoffe der Zukunft - Innovative Methoden und neue Modalitäten in der Medizinischen Chemie (494832089) (494832089)

Experiment(s):

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

Appears in the scientific report 2024

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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 ; Index Chemicus ; Nationallizenz ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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