2. Academic Validation
  3. TMPRSS2 Inhibitor Discovery Facilitated through an In Silico and Biochemical Screening Platform

TMPRSS2 Inhibitor Discovery Facilitated through an In Silico and Biochemical Screening Platform

  • ACS Med Chem Lett. 2023 May 30;14(6):860-866. doi: 10.1021/acsmedchemlett.3c00035.
Amanda L Peiffer 1 2,  Julie M Garlick 1 3,  Yujin Wu 3,  Jesse W Wotring 4,  Sahil Arora 3,  Alexander S Harmata 3,  Daniel A Bochar 3,  Corey J Stephenson 3,  Matthew B Soellner 2 3,  Jonathan Z Sexton 4 5,  Charles L Brooks 3rd 2 3 6,  Anna K Mapp 1 2 3
Affiliations

Affiliations

  • 1 Life Sciences Institute, University of Michigan, Ann Arbor, Michigan 48019, United States.
  • 2 Program in Chemical Biology, University of Michigan, Ann Arbor, Michigan 48109, United States.
  • 3 Department of Chemistry, University of Michigan, Ann Arbor, Michigan 48109, United States.
  • 4 Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109, United States.
  • 5 University of Michigan Medical School, Ann Arbor, Michigan 48109, United States.
  • 6 Department of Biophysics, University of Michigan, Ann Arbor, Michigan 48109, United States.
PMID: 37284689 DOI: 10.1021/acsmedchemlett.3c00035
Abstract

The COVID-19 pandemic has highlighted the need for new Antiviral approaches because many of the currently approved drugs have proven ineffective against mitigating SARS-CoV-2 infections. The host transmembrane serine protease TMPRSS2 is a promising Antiviral target because it plays a role in priming the spike protein before viral entry occurs for the most virulent variants. Further, TMPRSS2 has no established physiological role, thereby increasing its attractiveness as a target for Antiviral agents. Here, we utilize virtual screening to curate large libraries into a focused collection of potential inhibitors. Optimization of a recombinant expression and purification protocol for the TMPRSS2 peptidase domain facilitates subsequent biochemical screening and characterization of selected compounds from the curated collection in a kinetic assay. In doing so, we identify new noncovalent TMPRSS2 inhibitors that block SARS-CoV-2 infectivity in a cellular model. One such inhibitor, debrisoquine, has high ligand efficiency, and an initial structure-activity relationship study demonstrates that debrisoquine is a tractable hit compound for TMPRSS2.

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