title: NMR-based discovery of lead inhibitors that block DNA binding of the human papillomavirus E2 protein.
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.
authors.affiliation: Pharmaceutical Products Division, Abbott Laboratories, Abbott Park, Illinois 60064-3500, USA.
authors.forename: P J
authors.initials: PJ
authors.lastname: Hajduk
authors.forename: J
authors.initials: J
authors.lastname: Dinges
authors.forename: G F
authors.initials: GF
authors.lastname: Miknis
authors.forename: M
authors.initials: M
authors.lastname: Merlock
authors.forename: T
authors.initials: T
authors.lastname: Middleton
authors.forename: D J
authors.initials: DJ
authors.lastname: Kempf
authors.forename: D A
authors.initials: DA
authors.lastname: Egan
authors.forename: K A
authors.initials: KA
authors.lastname: Walter
authors.forename: T S
authors.initials: TS
authors.lastname: Robins
authors.forename: S B
authors.initials: SB
authors.lastname: Shuker
authors.forename: T F
authors.initials: TF
authors.lastname: Holzman
authors.forename: S W
authors.initials: SW
authors.lastname: Fesik
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D001713:Biphenyl Compounds / Q000494:pharmacology; D052688:Bovine papillomavirus 1; D018360:Crystallography, X-Ray; D004247:DNA / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015195:Drug Design; D006801:Humans; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008956:Models, Chemical; D008958:Models, Molecular; D027383:Papillomaviridae; D011487:Protein Conformation; D012097:Repressor Proteins / Q000378:metabolism*; D013329:Structure-Activity Relationship; D015534:Trans-Activators / Q000378:metabolism*; D014764:Viral Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000998:Antiviral Agents; D001713:Biphenyl Compounds; D004268:DNA-Binding Proteins; C051550:E2 protein, Bovine papillomavirus; D008024:Ligands; D012097:Repressor Proteins; D015534:Trans-Activators; D014764:Viral Proteins; D004247:DNA