Cyclic Peptidic Furin Inhibitors Developed by Combinatorial Chemistry

Area of Science:

• Biochemistry and Molecular Biology
• Medicinal Chemistry
• Protease Inhibitor Development

Background:

• Furin is a critical human serine protease involved in activating substrates essential for physiological processes.
• Dysregulation of furin activity is implicated in various pathologies, including cancer, inflammatory diseases, and infections.
• Developing effective furin inhibitors is a key therapeutic strategy.

Purpose of the Study:

• To discover novel, potent, and stable peptide inhibitors of the furin protease.
• To utilize a combinatorial chemistry approach based on the SFTI-1 trypsin inhibitor scaffold.
• To characterize the inhibitory activity and stability of newly synthesized furin inhibitors.

Main Methods:

• Employed a combinatorial chemistry approach to generate a library of 2000 peptides.
• Utilized the trypsin inhibitor SFTI-1 as a leading structure for inhibitor design.
• Synthesized and characterized mono- and bicyclic furin inhibitors, including molecular dynamics simulations.

Main Results:

• Identified five novel mono- or bicyclic peptide furin inhibitors with subnanomolar inhibitory constants (Ki).
• Compound 5 demonstrated the highest potency (Ki = 0.21 nM) and superior proteolytic resistance compared to existing inhibitors.
• Inhibitor 5 effectively reduced furin-like activity in PANC-1 cell lysate.

Conclusions:

• The study successfully generated highly potent and stable peptide inhibitors targeting furin.
• Compound 5 represents a promising therapeutic candidate for furin-mediated diseases.
• Further investigation into furin-inhibitor complexes via molecular dynamics provides structural insights.