Use of β-Amino Acids in the Design of Substrate-Based Peptidase Inhibitors
ß-Amino acids contain an extra carbon between the amino and carboxy-termini; this modification renders the adjacent peptide bond resistant to hydrolysis [1,2]. We hypothesize that substitution of the residues at the scissile bond with ß-amino acids can confer resistance to cleavage without necessarily abolishing binding to the enzyme. In the present study, we have synthesized a series of ß-amino acid-substituted analogues of bradykinin (BK), and examined both their susceptibility to cleavage by and their ability to inhibit the soluble metalloendopeptidases EC 188.8.131.52 (EP24.15) and EC 184.108.40.206 (EP24.16) . Our findings suggest that ß-amino acid incorporation at the scissile bond completely prevents peptide hydrolysis with only minimal reduction in affinity for the enzyme.