NMR-BASED DISCOVERY OF LEAD INHIBITORS THAT BLOCK DNA-BINDING OF THE HUMAN-PAPILLOMAVIRUS E2 PROTEIN

The E2 protein is required far the replication of human papillomavirus es (HPVs), which are responsible for anogenital warts and cervical car cinomas, Using an NMR-based screen, we tested compounds for binding to the DNA-binding domain of the HPV-E2 protein. Three classes of compou nds were identified which bound to two distinct sites on the protein. Biphenyl and biphenyl ether compounds containing a carboxylic acid bin d to a site near the DNA recognition helix and inhibit the binding of E2 to DNA. Benzophenone-containing compounds which lack a carboxylic a cid group bind to the beta-barrel formed by the dimer intel face and e xhibit negligible effects on the binding of E2 to DNA. Structure-activ ity relationships from the biphenyl and biphenyl ether compounds were combined to produce a compound [5-(3'-(3 '',5 ''-dichlorophenoxy)pheny l)-2,4-pentadienoic acid] with an IC50 value of approximately 10 mu M. This compound represents a useful lead for the development of antivir al agents that interfere with HPV replication and further illustrates the usefulness of the SAR by NMR method in the drug discovery process.