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Azapeptide-Based SARS-CoV-2 Main Protease Inhibitors: Design, Synthesis, Enzyme Inhibition, Structural Determination,

Philipp Flury1,2, Jyoti Vishwakarma3, Katharina Sylvester4

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New azapeptide inhibitors targeting SARS-CoV-2 main protease (Mpro) show potent antiviral activity. These compounds are effective against variants and demonstrate potential as broad-spectrum coronavirus therapeutics.

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Area of Science:

  • Biochemistry
  • Virology
  • Medicinal Chemistry

Background:

  • The SARS-CoV-2 main protease (Mpro) is crucial for viral replication and pathogenesis.
  • Mpro's conservation across coronaviruses makes it a promising target for broad-spectrum antiviral drugs.

Purpose of the Study:

  • To design, synthesize, and evaluate novel azapeptide-based inhibitors of SARS-CoV-2 Mpro.
  • To explore structure-activity relationships and identify potent antiviral compounds.

Main Methods:

  • Chemical synthesis of azapeptide derivatives.
  • Biochemical assays to determine Mpro inhibition (IC50 values).
  • Antiviral activity testing against SARS-CoV-2 variants and other coronaviruses.
  • Crystallographic analysis of Mpro-inhibitor complexes.

Main Results:

  • Several azapeptide inhibitors achieved nanomolar IC50 values against SARS-CoV-2 Mpro.
  • Compounds 14r, 14s, 20a, and 20g demonstrated significant inhibitory potency.
  • Selected inhibitors showed activity against MERS-CoV and SARS-CoV-1 Mpro, but not human cathepsin L.
  • Inhibitors like 20a and 20f exhibited potent antiviral activity, including against the E166V variant, comparable to nirmatrelvir.
  • Cocrystallization revealed a covalent adduct of 20a with the Mpro catalytic residue Cys145.

Conclusions:

  • Azapeptide-based inhibitors represent a promising class of compounds for targeting SARS-CoV-2 Mpro.
  • These inhibitors demonstrate broad-spectrum potential against various coronaviruses.
  • The identified compounds serve as valuable tools for developing future pan-anticoronaviral therapies.