Small molecule inhibitors of the human papillomavirus E1-E2 interaction.
Human papillomaviruses are responsible for multiple human diseases, including cervical cancer caused by multiple high-risk types and genital warts caused by the low-risk types 6 and 11. Based on the research indicating that low-risk HPV could be successfully targeted by inhibitors of viral DNA replication, we carried out several high-throughput screens for inhibitors of DNA replication activities. Two series were identified in screens for inhibitors of the interaction between the viral proteins E1 and E2. The two series were demonstrated to bind to overlapping sites on the transactivation domain of E2, at the E1-binding interface, by a series of biochemical and biophysical experiments. A member of the first series was also cocrystallized with the E2 transactivation domain. For both series, structure-activity investigations are described, which resulted in several hundred fold improvements in activity. The best compounds in each series had low nanomolar activity against the HPV11 E1-E2 interaction, and EC(50) values in cellular DNA replication assays of approximately 1 μM. Binding modes for the two series are compared, and some general conclusions about the discovery of protein-protein interaction inhibitors are drawn from the work described.
White
Peter W
PW
Boehringer Ingelheim Ltd, Canada. peter.white@boehringer-ingelheim.com
Faucher
Anne-Marie
AM
Goudreau
Nathalie
N
D000998:Antiviral Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D001665:Binding Sites; D002219:Carbamates / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D004353:Drug Evaluation, Preclinical / Q000379:methods; D006801:Humans; D007189:Indans / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D056004:Molecular Dynamics Simulation; D027383:Papillomaviridae / Q000235:genetics / Q000378:metabolism; D010880:Piperidines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D011487:Protein Conformation; D014764:Viral Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism
C413384:1,2-indanedione; D000998:Antiviral Agents; D002219:Carbamates; D004268:DNA-Binding Proteins; D007189:Indans; D010880:Piperidines; D014764:Viral Proteins; C072379:repaglinide