Ferrara, Bill T. ORCID: https://orcid.org/0000-0002-2163-4032, Gale, Thomas and Thompson, Elinor ORCID: https://orcid.org/0000-0002-6434-9290 (2025) C-terminal analogues of camostat retain TMPRSS2 protease in-hibition: new synthetic directions for antiviral repurposing of guanidinium-based drugs in respiratory infections. International Journal of Molecular Sciences. ISSN 1661-6596 (Print), 1422-0067 (Online) (In Press)

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Abstract

The recent global coronavirus pandemic highlighted the ever-present threat of respiratory virus outbreaks and the consequent need for ongoing research into antiviral therapy. To this end, structural analogues of the guani-dinium-based drug camostat mesylate have been synthesised to probe their potential inhibition of TMPRSS2, a human protease that is essential for infection by many respiratory viruses, including SARS-CoV2. Our in vitro-fluorescence-based protease assays and supporting computational docking studies sug-gest that C-terminal camostat analogues retain TMPRSS2 inhibition potencies (IC50 = 1-3 nM, BE = -6.6 to -7.0 kcal/mol) that match or exceed that of the parent drug. Analogues 1c and 1d emerged as lead candidates in this regard, thereby validating the rationale behind C-terminal structural modifications and highlighting these derivatives as promising scaf-folds for the future development of targeted antiviral therapeutics. Replacement of camo-stat’s ester functionality with peptide linkages largely preserves non-covalent binding but disrupts in vitro protease inhibition, findings consistent with the parent drug’s known role as an acylating suicide inhibitor. Docking studies confirm that replacement of aro-matic residues with flexible, equivalent length alkyl chains is detrimental to drug binding. These function and binding data offer new directions for the synthesis of further ana-logues of camostat and of other guanidinium-based protease inhibitors that have yet to be refined via structure-activity relationship studies. Further investigation will support tai-loring this class of drugs for repurposing in antiviral therapy.

Item Type:	Article
Uncontrolled Keywords:	Protease, sars cov2, inhibitor, camostat, serine protease
Subjects:	Q Science > Q Science (General)
Faculty / School / Research Centre / Research Group:	Faculty of Engineering & Science Faculty of Engineering & Science > School of Science (SCI)
Last Modified:	14 Jul 2025 09:03
URI:	https://gala.gre.ac.uk/id/eprint/50814

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