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rdf:type |
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lifeskim:mentions |
umls-concept:C0017797,
umls-concept:C0022914,
umls-concept:C0033607,
umls-concept:C0072323,
umls-concept:C0205460,
umls-concept:C0220781,
umls-concept:C0220825,
umls-concept:C0243126,
umls-concept:C0318467,
umls-concept:C0559956,
umls-concept:C1707689,
umls-concept:C1883254
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pubmed:issue |
7
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pubmed:dateCreated |
1999-5-20
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pubmed:abstractText |
The structure-based design, chemical synthesis, and biological evaluation of various human rhinovirus (HRV) 3C protease (3CP) inhibitors which incorporate P1 lactam moieties in lieu of an L-glutamine residue are described. These compounds are comprised of a tripeptidyl or peptidomimetic binding determinant and an ethyl propenoate Michael acceptor moiety which forms an irreversible covalent adduct with the active site cysteine residue of the 3C enzyme. The P1-lactam-containing inhibitors display significantly increased 3CP inhibition activity along with improved antirhinoviral properties relative to corresponding L-glutamine-derived molecules. In addition, several lactam-containing compounds exhibit excellent selectivity for HRV 3CP over several other serine and cysteine proteases and are not appreciably degraded by a variety of biological agents. One of the most potent inhibitors (AG7088, mean antirhinoviral EC90 approximately 0.10 microM, n = 46 serotypes) is shown to warrant additional preclinical development to explore its potential for use as an antirhinoviral agent.
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
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pubmed:status |
MEDLINE
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pubmed:month |
Apr
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pubmed:issn |
0022-2623
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pubmed:author |
pubmed-author:BrownE LEL,
pubmed-author:BurkeB JBJ,
pubmed-author:DragovichP SPS,
pubmed-author:FerreR ARA,
pubmed-author:FordC ECE,
pubmed-author:FuhrmanS ASA,
pubmed-author:HartJ CJC,
pubmed-author:HendricksonT FTF,
pubmed-author:KosaM BMB,
pubmed-author:LeeC ACA,
pubmed-author:MarakovitsJ TJT,
pubmed-author:MatthewsD ADA,
pubmed-author:MeadorJ WJW3rd,
pubmed-author:PatickA KAK,
pubmed-author:PrinsT JTJ,
pubmed-author:RejtoP APA,
pubmed-author:TuntlandTT,
pubmed-author:WebberS ESE,
pubmed-author:WorlandS TST,
pubmed-author:ZhouRR
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pubmed:issnType |
Print
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pubmed:day |
8
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pubmed:volume |
42
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
1213-24
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pubmed:dateRevised |
2008-4-23
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pubmed:meshHeading |
pubmed-meshheading:10197965-Antiviral Agents,
pubmed-meshheading:10197965-Cell Line,
pubmed-meshheading:10197965-Crystallography, X-Ray,
pubmed-meshheading:10197965-Cysteine Endopeptidases,
pubmed-meshheading:10197965-Cysteine Proteinase Inhibitors,
pubmed-meshheading:10197965-Drug Design,
pubmed-meshheading:10197965-Drug Evaluation, Preclinical,
pubmed-meshheading:10197965-Glutamine,
pubmed-meshheading:10197965-Humans,
pubmed-meshheading:10197965-Isoxazoles,
pubmed-meshheading:10197965-Lactams,
pubmed-meshheading:10197965-Models, Molecular,
pubmed-meshheading:10197965-Molecular Mimicry,
pubmed-meshheading:10197965-Oligopeptides,
pubmed-meshheading:10197965-Pyrrolidinones,
pubmed-meshheading:10197965-Rhinovirus,
pubmed-meshheading:10197965-Structure-Activity Relationship,
pubmed-meshheading:10197965-Viral Proteins
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pubmed:year |
1999
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pubmed:articleTitle |
Structure-based design, synthesis, and biological evaluation of irreversible human rhinovirus 3C protease inhibitors. 4. Incorporation of P1 lactam moieties as L-glutamine replacements.
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pubmed:affiliation |
Agouron Pharmaceuticals, Inc., 3565 General Atomics Court, San Diego, California 92121, USA.
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pubmed:publicationType |
Journal Article
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