title: Rational design and biochemical utility of specific inhibitors of angiotensin-converting enzyme.
abstract: Angiotensin-converting enzyme (ACE), the receptor for an important new class of antihypertensive drugs, is now one of the better studied zinc metallopeptidases. The development of several classes of tightly binding competitive inhibitors of ACE has led to increased understanding of the structure and function of this enzyme while also yielding important new drugs for the diagnosis and treatment of hypertensive disease. Peptides from snake venom provided the first proof of the therapeutic utility of ACE inhibitors, and a tripeptide sequence, Phe-Ala-Pro, was used as a model for sidechain interactions with ACE in the rational design of simpler nonpeptidic inhibitors such as captopril and enalapril. These and more recently developed ACE inhibitors can be classified according to their structural analogy to dipeptides or tripeptides and according to the nature of their zinc-binding ligands, such as sulfhydryl, ketone, carboxylate, or hydroxyphosphinyl, that contribute greatly to their binding to ACE. Several newer ACE inhibitors have increased potency and/or improved pharmacokinetic properties due to modifications such as substitution of the proline ring or replacement of the methyl side chain analogous to Ala by an aminobutyl residue analogous to Lys. The availability of structurally diverse ACE inhibitors with great potency and specificity provides a powerful biochemical tool for purification, localization, and characterization of ACE in different tissues, and for distinguishing related zinc metallopeptidases with similar properties.
authors.affiliation: Squibb Institute for Medical Research, Princeton, New Jersey 08543-4000.
authors.forename: D W
authors.initials: DW
authors.lastname: Cushman
authors.forename: M A
authors.initials: MA
authors.lastname: Ondetti
authors.forename: E M
authors.initials: EM
authors.lastname: Gordon
authors.forename: S
authors.initials: S
authors.lastname: Natarajan
authors.forename: D S
authors.initials: DS
authors.lastname: Karanewsky
authors.forename: J
authors.initials: J
authors.lastname: Krapcho
authors.forename: E W
authors.initials: EW
authors.lastname: Petrillo
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D004151:Dipeptides / Q000494:pharmacology; D015195:Drug Design; D006801:Humans; D010455:Peptides / Q000494:pharmacology; D007703:Peptidyl-Dipeptidase A / Q000302:isolation & purification; D011392:Proline / Q000737:chemistry; D012910:Snake Venoms / Q000494:pharmacology
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D004151:Dipeptides; D010455:Peptides; D012910:Snake Venoms; D011392:Proline; D007703:Peptidyl-Dipeptidase A