BPTI backbone variants and implications for inhibitory activity

Abstract

Structural variants of BPTI were synthesized en route an enzymatic-chemical semisynthesis. The P1-P2 amide bond of the inhibitor molecule, which, as donor, contributes a hydrogen bond towards trypsin in the enzyme-inhibitor complex, was replaced by either a ketomethylene function or an ester bond yielding molecules with inhibitory activity. The two backbone-mutated BPTI derivatives showed increased dissociation constants of their respective trypsin complexes, obviously due to the lack of a single hydrogen-bond interaction in the enzyme-inhibitor complex.