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

J Med Chem. 2024 Jun 13;67(11):8757-8790. doi: 10.1021/acs.jmedchem.4c00053. Epub 2024 May 16.

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.

MeSH terms

  • Antiviral Agents* / chemical synthesis
  • Antiviral Agents* / chemistry
  • Antiviral Agents* / pharmacology
  • COVID-19 Drug Treatment
  • Coronavirus 3C Proteases* / antagonists & inhibitors
  • Coronavirus 3C Proteases* / chemistry
  • Coronavirus 3C Proteases* / metabolism
  • Cysteine Proteinase Inhibitors / chemical synthesis
  • Cysteine Proteinase Inhibitors / chemistry
  • Cysteine Proteinase Inhibitors / pharmacology
  • Drug Discovery
  • Humans
  • Macrocyclic Compounds / chemical synthesis
  • Macrocyclic Compounds / chemistry
  • Macrocyclic Compounds / pharmacology
  • Nitriles* / chemical synthesis
  • Nitriles* / chemistry
  • Nitriles* / pharmacology
  • Peptides / chemical synthesis
  • Peptides / chemistry
  • Peptides / pharmacology
  • Peptidomimetics / chemical synthesis
  • Peptidomimetics / chemistry
  • Peptidomimetics / pharmacology
  • Protease Inhibitors / chemical synthesis
  • Protease Inhibitors / chemistry
  • Protease Inhibitors / pharmacology
  • SARS-CoV-2* / drug effects
  • Structure-Activity Relationship

Substances

  • Antiviral Agents
  • Nitriles
  • Coronavirus 3C Proteases
  • Macrocyclic Compounds
  • Protease Inhibitors
  • Peptidomimetics
  • Cysteine Proteinase Inhibitors
  • 3C-like proteinase, SARS-CoV-2
  • Peptides