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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
20
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pubmed:dateCreated |
1997-11-10
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pubmed:abstractText |
The E2 protein is required for the replication of human papillomaviruses (HPVs), which are responsible for anogenital warts and cervical carcinomas. Using an NMR-based screen, we tested compounds for binding to the DNA-binding domain of the HPV-E2 protein. Three classes of compounds were identified which bound to two distinct sites on the protein. Biphenyl and biphenyl ether compounds containing a carboxylic acid bind to a site near the DNA recognition helix and inhibit the binding of E2 to DNA. Benzophenone-containing compounds which lack a carboxylic acid group bind to the beta-barrel formed by the dimer interface and exhibit negligible effects on the binding of E2 to DNA. Structure-activity relationships from the biphenyl and biphenyl ether compounds were combined to produce a compound [5-(3'-(3",5"-dichlorophenoxy)-phenyl)-2,4-pentadienoic acid] with an IC50 value of approximately 10 microM. This compound represents a useful lead for the development of antiviral agents that interfere with HPV replication and further illustrates the usefulness of the SAR by NMR method in the drug discovery process.
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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 |
Sep
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pubmed:issn |
0022-2623
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pubmed:author |
pubmed-author:DingerMM,
pubmed-author:EganD ADA,
pubmed-author:FesikS WSW,
pubmed-author:HajdukP JPJ,
pubmed-author:HolzmanT FTF,
pubmed-author:KempfD JDJ,
pubmed-author:MerlockMM,
pubmed-author:MiddletonTT,
pubmed-author:MiknisG FGF,
pubmed-author:RobinsT STS,
pubmed-author:ShukerS BSB,
pubmed-author:WalterK AKA
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pubmed:issnType |
Print
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pubmed:day |
26
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pubmed:volume |
40
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
3144-50
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pubmed:dateRevised |
2006-11-15
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pubmed:meshHeading |
pubmed-meshheading:9379433-Antiviral Agents,
pubmed-meshheading:9379433-Binding Sites,
pubmed-meshheading:9379433-Biphenyl Compounds,
pubmed-meshheading:9379433-Bovine papillomavirus 1,
pubmed-meshheading:9379433-Crystallography, X-Ray,
pubmed-meshheading:9379433-DNA,
pubmed-meshheading:9379433-DNA-Binding Proteins,
pubmed-meshheading:9379433-Drug Design,
pubmed-meshheading:9379433-Humans,
pubmed-meshheading:9379433-Ligands,
pubmed-meshheading:9379433-Magnetic Resonance Spectroscopy,
pubmed-meshheading:9379433-Models, Chemical,
pubmed-meshheading:9379433-Models, Molecular,
pubmed-meshheading:9379433-Papillomaviridae,
pubmed-meshheading:9379433-Protein Conformation,
pubmed-meshheading:9379433-Repressor Proteins,
pubmed-meshheading:9379433-Structure-Activity Relationship,
pubmed-meshheading:9379433-Trans-Activators,
pubmed-meshheading:9379433-Viral Proteins
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pubmed:year |
1997
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pubmed:articleTitle |
NMR-based discovery of lead inhibitors that block DNA binding of the human papillomavirus E2 protein.
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pubmed:affiliation |
Pharmaceutical Products Division, Abbott Laboratories, Abbott Park, Illinois 60064-3500, USA.
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pubmed:publicationType |
Journal Article
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