title: Investigation of subsite preferences in aminopeptidase A (EC 3.4.11.7) led to the design of the first highly potent and selective inhibitors of this enzyme.
abstract: The study of the physiological roles of the membrane-bound zinc-aminopeptidase A (glutamyl aminopeptidase, EC 3.4.11.7) 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 fit 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 H(3)N(+)CH(CH(2)CH(2)SO(3)(-))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 CCK(8) in the central nervous system.
authors.affiliation: Département de Pharmacochimie Moléculaire et Structurale, INSERM U266 - CNRS UMR 8600, UFR des Sciences Pharmaceutiques et Biologiques, 4, avenue de l'Observatoire, 75270 Paris Cedex 06, France.
authors.forename: C
authors.initials: C
authors.lastname: David
authors.forename: L
authors.initials: L
authors.lastname: Bischoff
authors.forename: H
authors.initials: H
authors.lastname: Meudal
authors.forename: A
authors.initials: A
authors.lastname: Mothé
authors.forename: N
authors.initials: N
authors.lastname: De Mota
authors.forename: S
authors.initials: S
authors.lastname: DaNascimento
authors.forename: C
authors.initials: C
authors.lastname: Llorens-Cortes
authors.forename: M C
authors.initials: MC
authors.lastname: Fournié-Zaluski
authors.forename: B P
authors.initials: BP
authors.lastname: Roques
mesh_terms: D000626:Aminopeptidases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D018826:CD13 Antigens / Q000037:antagonists & inhibitors / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism*; D043384:Glutamyl Aminopeptidase; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D015260:Neprilysin / Q000378:metabolism; D007703:Peptidyl-Dipeptidase A / Q000187:drug effects / Q000378:metabolism; D011817:Rabbits; D051381:Rats; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D013237:Stereoisomerism; D013552:Swine
chemical_list: D004791:Enzyme Inhibitors; D011994:Recombinant Proteins; D000626:Aminopeptidases; D018826:CD13 Antigens; D043384:Glutamyl Aminopeptidase; D007703:Peptidyl-Dipeptidase A; D015260:Neprilysin