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dc.contributorWichita State University. Department of Chemistryen_US
dc.contributor.authorWei, Liuqingen_US
dc.contributor.authorLai, Zhongen_US
dc.contributor.authorGan, Xiangdongen_US
dc.contributor.authorAlliston, Kevin R.en_US
dc.contributor.authorZhong, Jiayingen_US
dc.contributor.authorEpp, Jeffrey B.en_US
dc.contributor.authorTu, Juanen_US
dc.contributor.authorPerera, Asiri B.en_US
dc.contributor.authorVan Stipdonk, Michael J.en_US
dc.contributor.authorGroutas, William C.en_US
dc.identifierHL 57788en_US
dc.identifier.citationArchives of biochemistry and biophysics. 2004 Sep 1; 429(1): 60-70.en_US
dc.descriptionClick on the DOI link below to access the article (may not be free).en_US
dc.description.abstractWe describe herein the design and in vitro biochemical evaluation of a novel class of mechanism-based inhibitors of human leukocyte elastase (HLE) that inactivate the enzyme via an unprecedented enzyme-induced sulfonamide fragmentation cascade. The inhibitors incorporate in their structure an appropriately functionalized saccharin scaffold. Furthermore, the inactivation of the enzyme by these inhibitors was found to be time-dependent and to involve the active site. Biochemical, HPLC, and mass spectrometric studies show that the interaction of these inhibitors with HLE results in the formation of a stable acyl complex and is accompanied by the release of (L) phenylalanine methyl ester. The data are consistent with initial formation of a Michaelis-Menten complex and subsequent formation of a tetrahedral intermediate with the active site serine (Ser(195)). Collapse of the tetrahedral intermediate with tandem fragmentation results in the formation of a highly reactive conjugated sulfonyl imine which can either react with water to form a stable acyl enzyme and/or undergo a Michael addition reaction with an active site nucleophilic residue (His(57)). It is also demonstrated herein that this class of compounds can be used in the design of inhibitors of serine proteases having either a neutral or basic primary substrate specificity. Thus, the results suggest that these inhibitors constitute a potential general class of mechanism-based inhibitors of (chymo)trypsin-like serine proteases.en_US
dc.description.sponsorshipNHLBI NIH HHSen_US
dc.relation.ispartofseriesArchives of biochemistry and biophysicsen_US
dc.relation.ispartofseriesArch. Biochem. Biophys.en_US
dc.subjectResearch Support, Non-U.S. Gov'ten_US
dc.subjectResearch Support, U.S. Gov't, P.H.S.en_US
dc.subject.meshDrug Designen_US
dc.subject.meshEnzyme Activationen_US
dc.subject.meshEnzyme Inhibitors/chemical synthesisen_US
dc.subject.meshLeukocyte Elastase/antagonists & inhibitorsen_US
dc.subject.meshSubstrate Specificityen_US
dc.subject.meshEnzyme Inhibitors/chemistryen_US
dc.subject.meshLeukocyte Elastase/chemistryen_US
dc.titleMechanism-based inactivation of human leukocyte elastase via an enzyme-induced sulfonamide fragmentation processen_US
dc.coverage.spacialUnited Statesen_US
dc.description.versionpeer revieweden_US
dc.rights.holderCopyright © 2004, Elsevieren_US

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