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A Fluorogenic Peptide Cleavage Assay to Screen for Proteolytic Activity: Applications for coronavirus spike protein activation
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Discovery of First-in-Class PROTAC Degraders of SARS-CoV-2 Main Protease

Yugendar R Alugubelli1, Jing Xiao1, Kaustav Khatua1

  • 1Texas A&M Drug Discovery Center, Department of Chemistry, Texas A&M University, College Station, Texas 77843, United States.

Journal of Medicinal Chemistry
|April 12, 2024
PubMed

Insights

New antivirals targeting the main protease (MPro) of coronaviruses show promise. This study demonstrates a novel proteolysis targeting chimera (PROTAC) approach to degrade MPro, offering potential against drug-resistant SARS-CoV-2 variants.

Area of Science:

  • Virology
  • Drug Discovery
  • Molecular Biology

Background:

  • Coronaviruses (CoVs) have caused significant outbreaks, including the COVID-19 pandemic.
  • The main protease (MPro) is crucial for viral replication and a key target for antiviral therapies.
  • Existing antivirals face challenges with drug resistance.

Purpose of the Study:

  • To develop a novel class of small-molecule antivirals using proteolysis targeting chimera (PROTAC) technology.
  • To investigate the degradation of SARS-CoV-2 main protease (MPro) via targeted protein degradation.
  • To evaluate the antiviral efficacy of MPro-targeting PROTACs against SARS-CoV-2, including drug-resistant strains.

Main Methods:

  • Development of proteolysis targeting chimera (PROTAC) molecules designed to induce MPro degradation.
  • Assessment of MPro protein level reduction in cell lines (e.g., 293T, A549-ACE2) using MPD2.
  • Investigation of the degradation mechanism (time-dependent, CRBN-mediated, proteasome-driven).
  • Evaluation of antiviral activity against SARS-CoV-2 strains and nirmatrelvir-resistant variants.

Main Results:

  • MPD2 effectively reduced MPro protein levels in 293T cells through a CRBN- and proteasome-dependent pathway.
  • MPD2 demonstrated significant efficacy in diminishing MPro levels in SARS-CoV-2-infected A549-ACE2 cells.
  • MPD2 exhibited potent antiviral activity against multiple SARS-CoV-2 strains.
  • Enhanced potency was observed against nirmatrelvir-resistant SARS-CoV-2 viruses.

Conclusions:

  • Targeted protein degradation of SARS-CoV-2 MPro represents a viable and innovative antiviral strategy.
  • PROTAC technology offers a promising approach for developing new therapeutics against coronaviruses.
  • This strategy holds potential for combating current and future drug-resistant viral variants.

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