Cyclic Peptidic Furin Inhibitors Developed by Combinatorial Chemistry

Agata Gitlin-Domagalska; Dawid Dębowski; Aleksandra Maciejewska; Sergey Samsonov; Martyna Maszota-Zieleniak; Natalia Ptaszyńska; Anna Łęgowska; Krzysztof Rolka

doi:10.1021/acsmedchemlett.3c00008

Cyclic Peptidic Furin Inhibitors Developed by Combinatorial Chemistry

ACS Med Chem Lett. 2023 Mar 15;14(4):458-465. doi: 10.1021/acsmedchemlett.3c00008. eCollection 2023 Apr 13.

Authors

Agata Gitlin-Domagalska¹, Dawid Dębowski¹, Aleksandra Maciejewska¹, Sergey Samsonov², Martyna Maszota-Zieleniak², Natalia Ptaszyńska¹, Anna Łęgowska¹, Krzysztof Rolka¹

Affiliations

¹ Department of Molecular Biochemistry, Faculty of Chemistry, University of Gdańsk, 80-308 Gdańsk, Poland.
² Department of Theoretical Chemistry, Faculty of Chemistry, University of Gdańsk, 80-308 Gdańsk, Poland.

Abstract

Furin is a human serine protease responsible for activating numerous physiologically relevant cell substrates and is also involved in the development of various pathological conditions, including inflammatory diseases, cancers, and viral and bacterial infections. Therefore, compounds with the ability to inhibit furin's proteolytic action are regarded as potential therapeutics. Here we took the combinatorial chemistry approach (library consisting of 2000 peptides) to obtain new, strong, and stable peptide furin inhibitors. The extensively studied trypsin inhibitor SFTI-1 was used as a leading structure. A selected monocylic inhibitor was further modified to finally yield five mono- or bicyclic furin inhibitors with values of K _i in the subnanomolar range. Inhibitor 5 was the most active (K _i = 0.21 nM) and significantly more proteolytically resistant than the reference furin inhibitor described in the literature. Moreover, it reduced furin-like activity in PANC-1 cell lysate. Detailed analysis of furin-inhibitor complexes using molecular dynamics simulations is also reported.