Accueil > Publications > Recherche par années > Années 1990 > 1999

David, C ; Bischoff, L ; Meudal, H ; Mothe, A ; De Mota, N ; DaNascimento, S ; Llorens-Cortes, C ; Fournie-Zaluski, MC ; Roques, BP

Investigation of subsite preferences in aminopeptidase A (EC led to the design of the first highly potent and selective inhibitors of this enzyme

Journal of Medicinal Chemistry 42 (25) 5197-5211

par Administrateur - publié le

Abstract :

The study of the physiological roles of the membrane-bound zinc-aminopeptidase A (glutamyl aminopeptidase, EC needs the design of efficient and selective inhibitors of this enzyme. An acute exploration of aminopeptidase A active site was performed by a combinatorial approach using (3-amino-2-mercapto-acyl)dipeptides able to sc its S-1, S-1’, and S-2’ subsites. This analysis confirmed that the S-1 subsite is optimally blocked by a glutamate or isosteric residues and demonstrated that the S-1’ subsite is hydrophobic whereas the S-2’ subsite recognizes preferentially negatively charged residues derived from aspartic acid. The optimization of these structural parameters led to the synthesis of nanomolar and subnanomolar inhibitors of aminopeptidase A such as H3N+CH(CH2CH2SO3-)CH(SH)CO-Ile-(3-COOH)Pro that exhibits a K-i of 0.87 nM. The best compounds were synthesized by a stereochemically controlled route. These first described highly potent inhibitors could allow studies about the role of physiological substrates of APA such as angiotensin II- and cholecystokinin CCK8 in the central nervous system.