NMR-based discovery of lead inhibitors that block DNA binding of the human papillomavirus E2 protein - PubMed (original) (raw)

. 1997 Sep 26;40(20):3144-50.

doi: 10.1021/jm9703404.

J Dinges, G F Miknis, M Merlock, T Middleton, D J Kempf, D A Egan, K A Walter, T S Robins, S B Shuker, T F Holzman, S W Fesik

Affiliations

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

P J Hajduk et al. J Med Chem. 1997.

Abstract

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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