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
  • 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.