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Structural analysis of experimental drugs binding to the SARS-CoV-2 target TMPRSS2.

Authors
  • Huggins, David J1
  • 1 Tri-Institutional Therapeutics Discovery Institute, New York, NY, USA; Department of Physiology and Biophysics, Weill Cornell Medical College of Cornell University, New York, NY, USA. Electronic address: [email protected]
Type
Published Article
Journal
Journal of molecular graphics & modelling
Publication Date
Aug 11, 2020
Volume
100
Pages
107710–107710
Identifiers
DOI: 10.1016/j.jmgm.2020.107710
PMID: 32829149
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

The emergence of SARS-CoV-2 has prompted a worldwide health emergency. There is an urgent need for therapeutics, both through the repurposing of approved drugs and the development of new treatments. In addition to the viral drug targets, a number of human drug targets have been suggested. In theory, targeting human proteins should provide an advantage over targeting viral proteins in terms of drug resistance, which is commonly a problem in treating RNA viruses. This paper focuses on the human protein TMPRSS2, which supports coronavirus life cycles by cleaving viral spike proteins. The three-dimensional structure of TMPRSS2 is not known and so we have generated models of the TMPRSS2 in the apo state as well as in complex with a peptide substrate and putative inhibitors to aid future work. Importantly, many related human proteases have 80% or higher identity with TMPRSS2 in the S1-S1' subsites, with plasminogen and urokinase-type plasminogen activator (uPA) having 95% identity. We highlight 376 approved, investigational or experimental drugs targeting S1A serine proteases that may also inhibit TMPRSS2. Whilst the presence of a relatively uncommon lysine residue in the S2/S3 subsites means that some serine protease inhibitors will not inhibit TMPRSS2, this residue is likely to provide a handle for selective targeting in a focused drug discovery project. We discuss how experimental drugs targeting related serine proteases might be repurposed as TMPRSS2 inhibitors to treat coronaviruses. Copyright © 2020 Elsevier Inc. All rights reserved.

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