Analogues of trypsin inhibitor SFTI-1 modified in the conserved P₁' position by synthetic or non-proteinogenic amino acids retain their inhibitory activity

Abstract

A series of linear and monocyclic (with a disulfide bridge only) analogues of trypsin inhibitor SFTI-1 modified in the P₁ and/or P₁' positions were synthesized by the solid-phase method. In the substrate specificity P₁ position, Phe or N-benzylglycine (Nphe) were introduced, whereas the conserved Ser6 in Bownam-Birk (BBI) inhibitors was replaced by Hse (L-homoserine), Nhse [N-(2-hydroxyethyl)glycine], Sar, and Ala. Kinetic studies of interaction of the analogues with bovine α-chymotrypsin have shown that in monocyclic (but not linear) analogues, Hse and Nhse are tolerated to afford potent inhibitors. This is the first evidence that the absolutely conserved Ser present in the inhibitor's P₁' position can be successfully replaced by a synthetic derivative.