Cyclic Peptidic Furin Inhibitors Developed by Combinatorial Chemistry

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 Ki in the subnanomolar range. Inhibitor 5 was the most active (Ki = 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.

Automated summary

In this study, five new peptide furin inhibitors with strong inhibitory action and stability were obtained using combinatorial chemistry. Inhibitor 5 showed the highest activity and was more resistant to proteolysis compared to the reference furin inhibitor described in the literature. It also reduced furin-like activity in PANC-1 cell lysate. Molecular dynamics simulations were performed to analyze the furin-inhibitor complexes in detail.