We hypothesize that substitution of α‐amino acids at or around the scissile bond of a peptide substrate with β‐amino acids (containing an extra carbon in the peptide backbone) will confer resistance to proteolytic cleavage without necessarily abolishing enzyme binding; indeed, such a stabilized analogue may act as a specific inhibitor of the peptidase. To test this possibility, we synthesised a series of β‐amino acid‐containing bradykinin analogues and examined their degradation by the soluble metalloendopeptidase EC 3.4.24.15. Inclusion of a β‐amino acid at or near the cleavage site of bradykinin completely prevented degradation by this enzyme. Furthermore, such analogues could still act as competitive inhibitors, with the most potent peptides exhibiting affinities for recombinant EC 3.4.24.15 only 1.5‐ to 2.5‐fold lower than bradykinin itself. Interestingly, these analogues also acted as agonists at the B2 bradykinin receptor in coronary artery segments, although their potencies were 2–3 orders of magnitude less than the native peptide. In conclusion, substitution of β‐amino acids at the scissile bond can stabilize peptides against hydrolysis with only a moderate decrease in enzyme affinity. Thus, peptidomimetics incorporating β‐amino acids may have utility in the design and development of novel, specific, substrate‐based peptidase inhibitors.

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