
==== Front
bioRxiv
BIORXIV
bioRxiv
2692-8205
Cold Spring Harbor Laboratory

10.1101/2024.08.28.609965
preprint
1
Article
Development of ketobenzothiazole-based peptidomimetic TMPRSS13 inhibitors with low nanomolar potency
Joushomme Alexandre http://orcid.org/0000-0002-7773-1560

Désilets Antoine http://orcid.org/0000-0001-5081-5564

Champagne William
Hassanzadeh Malihe
Lemieux Gabriel http://orcid.org/0000-0002-2313-5528

Gravel-Trudeau Alice
Lepage Matthieu http://orcid.org/0009-0004-4613-3906

Lafrenière Sabrina
Froehlich Ulrike
List Karin http://orcid.org/0000-0002-5847-5637

Boudreault Pierre-Luc http://orcid.org/0000-0002-2032-7970

Leduc Richard http://orcid.org/0000-0001-6854-8003

29 8 2024
2024.08.28.609965https://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which allows reusers to copy and distribute the material in any medium or format in unadapted form only, for noncommercial purposes only, and only so long as attribution is given to the creator.
http://biorxiv.org/lookup/doi/10.1101/2024.08.28.609965
nihpp-2024.08.28.609965.pdf
Abstract

TMPRSS13, a member of the Type II Transmembrane Serine Proteases (TTSP) family, is involved in cancer progression and in cell entry of respiratory viruses. To date, no inhibitors have been specifically developed toward this protease. In this study, a chemical library of 65 ketobenzothiazole-based peptidomimetic molecules was screened against a proteolytically active form of recombinant TMPRSS13 to identify novel inhibitors. Following an initial round of screening, subsequent synthesis of additional derivatives supported by molecular modelling, uncovered important molecular determinants involved in TMPRSS13 inhibition. One inhibitor, N-0430, achieved low nanomolar affinity towards TMPRSS13 activity in a cellular context. Using a SARS-CoV-2 pseudovirus cell entry model, we further show the ability of N-0430 to block TMPRSS13-dependent entry of the pseudovirus. The identified peptidomimetic inhibitors and the molecular insights of their potency gained from this study will aid in the development of specific TMPRSS13 inhibitors.
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pmc
