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Inhibitors of tripeptidyl peptidase II. 2. Generation of the first novel lead inhibitor of cholecystokinin-8-inactivating peptidase: A strategy for the design of peptidase inhibitors

Ganellin, CR; Bishop, PB; Bambal, RB; Chan, SMT; Law, JK; Marabout, B; ... Schwartz, JC; + view all (2000) Inhibitors of tripeptidyl peptidase II. 2. Generation of the first novel lead inhibitor of cholecystokinin-8-inactivating peptidase: A strategy for the design of peptidase inhibitors. Journal of Medicinal Chemistry , 43 (4) 664 - 674.

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Abstract

The cholecystokinin-8 (CCK-8)-inactivating peptidase is a serine peptidase which has been shown to be a membrane-bound isoform of tripeptidyl peptidase II (EC 3.4.14.10). It cleaves the neurotransmitter CCK-8 sulfate at the Met-Gly bond to give Asp-Tyr(SO3H)-Met-OH + Gly-Trp-Met-Asp-Phe-NH2. In seeking a reversible inhibitor of this peptidase, the enzymatic binding subsites were characterized using a fluorimetric assay based on the hydrolysis of the artificial substrate Ala-Ala-Phe- amidomethylcoumarin. A series of di- and tripeptides having various alkyl or aryl side chains was studied to determine the accessible volume for binding and to probe the potential for hydrophobic interactions. From this initial study the tripeptides Ile-Pro-Ile-OH (K-i = 1 mu M) and Ala-Pro-Ala-OH (K-i = 3 mu M) and dipeptide amide Val-Nvl-NHBu (K-i = 3 mu M) emerged as leads. Comparison of these structures led to the synthesis of Val-Pro-NHBu (K-i = 0.57 mu M) which served for later optimization in the design of butabindide, a potent reversible competitive and selective inhibitor of the CCK-8- inactivating peptidase. The strategy for this work is explicitly described since it illustrates a possible general approach for peptidase inhibitor design

Type:Article
Title:Inhibitors of tripeptidyl peptidase II. 2. Generation of the first novel lead inhibitor of cholecystokinin-8-inactivating peptidase: A strategy for the design of peptidase inhibitors
Additional information:Journal Article FEB 24 287LR Ganellin CR Univ London Univ Coll, Dept Chem, 20 Gordon St, London WC1H 0AJ, England J MED CHEM
Keywords:ALKYL, As, ASSAY, BINDING, BOND, BRAIN-SLICES, C-TERMINAL OCTAPEPTIDE, CCK-A AGONISTS, comparison, DECREASES FOOD-INTAKE, design, ENDOGENOUS CHOLECYSTOKININ, ENKEPHALINASE INHIBITOR, GENERATION, Hydrolysis, INHIBITOR, INHIBITORS, interaction, MED, neurotransmitter, novel, optimization, POTENT, PROBE, reversible, SATIETY, SERIES, Serine, SERINE PEPTIDASE, strategies, strategy, Structure, SUBSTRATE, SUBSTRATE-SPECIFICITY, synthesis, volume
UCL classification:UCL > School of BEAMS > Faculty of Maths and Physical Sciences > Chemistry

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