title: Sulfamide-based inhibitors for carboxypeptidase A. Novel type transition state analogue inhibitors for zinc proteases.
abstract: N-Sulfamoylphenylalanine and its derivatives having varied alkyl groups on the terminal amino group were designed rationally as transition state analogue inhibitors for carboxypeptidase A (CPA) and synthesized. In CPA inhibitory assays the parent compound having the (S)-configuration, i.e., (S)-1a, showed potent inhibitory activity with the K(i) value of 0.64 microM. Its enantiomer was shown to be much less potent (K(i) = 470 microM). Introduction of an alkyl group such as methyl or isopropyl group on the terminal amino group of (S)-1a lowered the inhibitory potency drastically. Introduction of a methyl group on the internal amino group of (S)-1a also caused a drastic reduction of the inhibitory activity. The structure of the CPA x(S)-1a complex determined by single-crystal X-ray diffraction reveals that the sulfamoyl moiety interacts with the zinc ion and functional groups at the active site of CPA, which is reminiscent of the postulated stabilization mode of a tetrahedral transition state in the CPA-catalyzed hydrolysis of a peptide substrate. On the basis of the design rationale and the binding mode of (S)-1a to CPA shown by X-ray crystallographic analysis, the present inhibitors are inferred to be a novel type of transition state analogue inhibitor for CPA.
authors.affiliation: Center for Integrated Molecular Systems, Division of Molecular and Life Sciences, Pohang University of Science and Technology, San 31 Hyoja-dong, Namku, Pohang 790-784 Korea.
authors.forename: Jung Dae
authors.initials: JD
authors.lastname: Park
authors.forename: Dong H
authors.initials: DH
authors.lastname: Kim
authors.forename: Seung-Jun
authors.initials: SJ
authors.lastname: Kim
authors.forename: Joo-Rang
authors.initials: JR
authors.lastname: Woo
authors.forename: Seong Eon
authors.initials: SE
authors.lastname: Ryu
mesh_terms: D002268:Carboxypeptidases / Q000037:antagonists & inhibitors*; D043422:Carboxypeptidases A; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D008958:Models, Molecular; D015394:Molecular Structure; D010649:Phenylalanine / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry; D015032:Zinc
chemical_list: D004791:Enzyme Inhibitors; C469564:N-sulfamoylphenylalanine benzyl ester; D013449:Sulfonamides; D010649:Phenylalanine; D002268:Carboxypeptidases; D043422:Carboxypeptidases A; D015032:Zinc