LATENT INHIBITORS .10. THE INHIBITION OF CARBOXYPEPTIDASE-A BY TETRAPEPTIDE ANALOGS BASED ON 1-AMINOCYCLOPROPANE CARBOXYLIC-ACID

In order to test the phenomenon of substrate activation of irreversibl e inhibition of carboxypeptidase A, extended inhibitors were designed. The synthesis of two N-protected tetrapeptide analogues containing C- terminal sulphones and l-aminocyolopropane carboxylic acid and one sim ilar N-unprotected tetrapeptide with C-terminal phenylalanine is descr ibed. The compounds were evaluated as inhibitors of carboxypeptidase A . The tetrapeptide sulphones exhibited time-dependent inhibition follo wing the unusual 'substrate activated' pattern of related dipeptides b ut the Phenylalanine containing dipeptide behaved as a mixed non-compe titive 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 properti es. A mechanism for the inhibition reactions of dipeptide and tetrapep tide analogues is proposed.