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dc.contributorWichita State University. Department of Chemistryen_US
dc.contributor.authorGroutas, William C.en_US
dc.contributor.authorKuang, Rongzeen_US
dc.contributor.authorVenkataraman, Radhikaen_US
dc.contributor.authorEpp, Jeffrey B.en_US
dc.contributor.authorRuan, Sumeien_US
dc.contributor.authorPrakash, Omen_US
dc.identifierHL 38048en_US
dc.identifier.citationBiochemistry. 1997 Apr 22; 36(16): 4739-50.en_US
dc.descriptionClick on the DOI link below to access the article (may not be free).en_US
dc.description.abstractWe describe in this paper the structure-based design of a general class of heterocyclic mechanism-based inhibitors of the serine proteinases that embody in their structure a novel peptidomimetic scaffold (1,2,5-thiadiazolidin-3-one 1,1-dioxide). Sulfone derivatives of this class (I) were found to be time-dependent, potent, and highly efficient irreversible inhibitors of human leukocyte elastase, cathepsin G, and proteinase 3. The partition ratios for a select number of inhibitors were found to range between 0 and 1. We furthermore demonstrate that these inhibitors exhibit remarkable enzyme selectivity that is dictated by the nature of the P1 residue and is consistent with the known substrate specificity reported for these enzymes. Thus, inhibitors with small hydrophobic side chains were found to be effective inhibitors of elastase, those with aromatic side chains of cathepsin G, and those with a basic side chain of bovine trypsin. Taken together, the findings cited herein reveal the emergence of a general class of stable mechanism-based inhibitors of the serine proteinases which can be readily synthesized using amino acid precursors. Biochemical and high-field NMR studies show that the interaction of this class of inhibitors with a serine proteinase results in the formation of a stable acyl complex(es) and the release of benzenesulfinate, formaldehyde, and a low molecular weight heterocycle. The data are consistent with initial formation of a Michaelis-Menten complex, acylation of Ser195, and tandem loss of the leaving group. The initial HLE-inhibitor complex reacts with water generating formaldehyde and a stable HLE-inhibitor complex. Whether the initial HLE-inhibitor complex also reacts with His57 to form a third complex is not known at this point. The desirable salient parameters associated with this class of inhibitors, including the expeditious generation of structurally diverse libraries of inhibitors based on I, suggest that this class of mechanism-based inhibitors is of general applicability and can be used in the development of inhibitors of human and viral serine proteinases of clinical relevance.en_US
dc.description.sponsorshipNHLBI NIH HHSen_US
dc.publisherAmerican Chemical Societyen_US
dc.subjectResearch Support, Non-U.S. Gov'ten_US
dc.subjectResearch Support, U.S. Gov't, P.H.S.en_US
dc.subject.meshAmino Acidsen_US
dc.subject.meshCathepsin Gen_US
dc.subject.meshCathepsins/antagonists & inhibitorsen_US
dc.subject.meshDrug Designen_US
dc.subject.meshHeterocyclic Compounds/chemistryen_US
dc.subject.meshLeukocyte Elastase/antagonists & inhibitorsen_US
dc.subject.meshMagnetic Resonance Spectroscopyen_US
dc.subject.meshModels, Molecularen_US
dc.subject.meshSerine Endopeptidases/metabolismen_US
dc.subject.meshSerine Proteinase Inhibitors/chemical synthesisen_US
dc.subject.meshStructure-Activity Relationshipen_US
dc.titleStructure-based design of a general class of mechanism-based inhibitors of the serine proteinases employing a novel amino acid-derived heterocyclic scaffolden_US
dc.coverage.spacialUnited Statesen_US
dc.description.versionpeer revieweden_US
dc.rights.holderCopyright © 1997 American Chemical Societyen_US

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