NMR-based discovery of lead inhibitors that block DNA binding of the human papillomavirus E2 protein.
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.
Hajduk
P J
PJ
Pharmaceutical Products Division, Abbott Laboratories, Abbott Park, Illinois 60064-3500, USA.
Dinges
J
J
Miknis
G F
GF
Merlock
M
M
Middleton
T
T
Kempf
D J
DJ
Egan
D A
DA
Walter
K A
KA
Robins
T S
TS
Shuker
S B
SB
Holzman
T F
TF
Fesik
S W
SW
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
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