NMR-based discovery of lead inhibitors that block DNA binding of the human papillomavirus E2 protein.

Hajduk PJ, Dinges J, Miknis GF, Merlock M, Middleton T, Kempf DJ, Egan DA, Walter KA, Robins TS, Shuker SB, Holzman TF, Fesik SW
J Med Chem. 1997 40 (20): 3144-50

PMID: 9379433 · DOI:10.1021/jm9703404

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.

MeSH Terms (19)

Antiviral Agents Binding Sites Biphenyl Compounds Bovine papillomavirus 1 Crystallography, X-Ray DNA DNA-Binding Proteins Drug Design Humans Ligands Magnetic Resonance Spectroscopy Models, Chemical Models, Molecular Papillomaviridae Protein Conformation Repressor Proteins Structure-Activity Relationship Trans-Activators Viral Proteins

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