Macrocyclic Azapeptide Nitriles: Structure-Based Discovery of Potent SARS-CoV-2 Main Protease Inhibitors as Antiviral Drugs

  • J Med Chem. 2024 May 16. doi: 10.1021/acs.jmedchem.4c00053.
Julian Breidenbach  1 ,  Rabea Voget  1 ,  Yaoyao Si  1 ,  Alexandra Hingst  1 ,  Tobias Claff  1 ,  Katharina Sylvester  1 ,  Valentina Wolf  1 ,  Vesa Krasniqi  1 ,  Abibe Useini  2 ,  Norbert Sträter  2 ,  Yukino Ogura  3 ,  Atsushi Kawaguchi  3 ,  Christa E Müller  1 ,  Michael Gütschow  1
Affiliations
  • 1. Pharmaceutical Institute, Pharmaceutical & Medicinal Chemistry, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany.
  • 2. Institute of Bioanalytical Chemistry, Center for Biotechnology and Biomedicine, Leipzig University, Deutscher Platz 5, 04103 Leipzig, Germany.
  • 3. Department of Infection Biology, Institute of Medicine, University of Tsukuba, 1-1-1 Tennodai, 305-8575 Tsukuba, Ibaraki, Japan.
PMID: 38753594 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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