Latent inhibitors Part 10. The inhibition of carboxypeptidase a by tetrapeptide analogues based on 1-aminocyclopropane carboxylic acid

In order to test the phenomenon of substrate activation of irreversible inhibition of carboxypeptidase A, extended inhibitors were designed. The synthesis of two N-protected tetrapeptide analogues containing C-terminal sulphones and 1-aminocyclopropane carboxylic acid and one similar N-unprotected tetrapeptide with C-terminal phenylalanine is described. The compounds were evaluated as inhibitors of carboxypeptidase A. The tetrapeptide sulphones exhibited time-dependent inhibition following the unusual 'substrate activated' pattern of related dipeptides but the phenylalanine containing dipeptide behaved as a mixed non-competitive inhibitor. A molecular modelling evaluation of the potential of aminocyclopropane carboxylic acid derivatives to act as irreversible inhibitors of peptidases was undertaken in an attempt to identify the properties of such compounds that lead to the unusual kinetic properties. A mechanism for the inhibition reactions of dipeptide and tetrapeptide analogues is proposed.