At least 20 million people in the US alone are infected with human papillomaviruses, which are associated with a wide range of pathologies, including external cutaneous warts, genital condylomata and cervical carcinoma. Nonetheless, there are no specific, beneficial antiviral therapies for this prevalent problem. In order to develop novel therapeutic approaches for compounds with antiviral activity against papillomaviruses, we have collaborated with Dr. Elliott Androphy of the Tufts University Medical Sch, who has cloned a novel cellular protein, provisionally named 42A. This protein interacts with the papillomavirus E2 transactivation and DNA replication regulator and appears to be required for activity. We propose experiments to determine the feasibility of inhibiting the E2-42A interaction as a means of developing novel antivirals. We plan to map the domains of the proteins responsible for their interaction and then use this information to design peptides which inhibit the interaction. The peptides will be assayed in systems we have developed to measure E2-dependent regulation and for antiviral and cytotoxic activities. These Phase I studies will thus allow us to determine the feasibility of developing high throughput screens for small- molecule inhibitors of th E2-42A interaction and the likelihood that they would be of use in inhibiting papillomavirus-related pathologies. PROPOSED COMMERCIAL APPLICATION: The proposed research will establish the feasibility of disrupting the HPV E2-42A complex as a means to attain antiviral activity. Results from this work will establish whether a drug discovery program based on this approach should be established to develop novel human papillomavirus-specific antivirals.
Thesaurus Terms:antiviral agent, drug design /synthesis /production, human papillomavirus, peptide structure, protein sequence, virus protein bovine papillomavirus, gene mutation, host organism interaction, transcription factor immunoprecipitation, tissue /cell cultureNational Institute of Allergy and Infectious Diseases (NIAID)
