Binding Loop Substitutions in the Cyclic Peptide SFTI‑1 Generate Potent and Selective Chymase Inhibitors

Chymase is a serine protease that
is predominantly expressed by
mast cells and has key roles in immune defense and the cardiovascular
system. This enzyme has also emerged as a therapeutic target for cardiovascular
disease due to its ability to remodel cardiac tissue and generate
angiotensin II. Here, we used the nature-derived cyclic peptide sunflower
trypsin inhibitor-1 (SFTI-1) as a template for designing novel chymase
inhibitors. The key binding contacts of SFTI-1 were optimized by combining
a peptide substrate library screen with structure-based design, which
yielded several variants with potent activity. The lead variant was
further modified by replacing the P1 Tyr residue with para-substituted Phe derivatives, generating new inhibitors with improved
potency (Ki = 1.8 nM) and higher selectivity
over closely related enzymes. Several variants were shown to block
angiotensin I cleavage in vitro, highlighting their potential for
further development and future evaluation as pharmaceutical leads.