Sulfamide-based inhibitors for carboxypeptidase A. Novel type transition state analogue inhibitors for zinc proteases.
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.
Park
Jung Dae
JD
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.
Kim
Dong H
DH
Kim
Seung-Jun
SJ
Woo
Joo-Rang
JR
Ryu
Seong Eon
SE
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
D004791:Enzyme Inhibitors; C469564:N-sulfamoylphenylalanine benzyl ester; D013449:Sulfonamides; D010649:Phenylalanine; D002268:Carboxypeptidases; D043422:Carboxypeptidases A; D015032:Zinc