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High-throughput Identification of Synergistic Drug Combinations by the Overlap2 Method
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Synergistic interactions of repurposed drugs that inhibit Nsp1, a major virulence factor for COVID-19

Hung-Teh Kao1, Andrew Orry2, Michael G Palfreyman3

  • 1Sypherion LLC, Providence, RI, 02903, USA. htkao@SypherionBio.com.

Scientific Reports
|June 17, 2022
PubMed

Insights

Scientists developed a new assay to detect the action of SARS-CoV-2

Area of Science:

  • Virology
  • Molecular Biology
  • Drug Discovery

Background:

  • The SARS-CoV-2 Nsp1 protein is a key virulence factor in COVID-19 pathogenesis.
  • Nsp1 interferes with host cell functions, contributing to disease severity.

Purpose of the Study:

  • To develop a novel assay for detecting Nsp1 activity in cultured lung cells.
  • To identify existing drugs that can inhibit Nsp1's detrimental effects.
  • To discover synergistic drug combinations for COVID-19 treatment.

Main Methods:

  • Development of a rapid multiplexed assay based on Nsp1-induced cytopathic effects.
  • Virtual screening of compounds targeting Nsp1's RNA-binding groove and C-terminal region.
  • Experimental screening of drug-repurposing candidates and their combinations.

Main Results:

  • Identification of multiple synergistic compound combinations that inhibit Nsp1 activity.
  • Ponatinib, Rilpivirine, and Montelukast demonstrated significant inhibition of Nsp1.
  • This combination reversed Nsp1's toxic effects comparably to genetic Nsp1 inactivation.

Conclusions:

  • A novel assay effectively measures Nsp1 activity and identifies inhibitors.
  • Drug repurposing strategies can yield effective combinations against Nsp1.
  • Ponatinib, Rilpivirine, and Montelukast represent a promising therapeutic combination for COVID-19.

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