PATHOGENIC PROTEIN INTERACTIONS

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Human papillomavirus (HPV) is the most common sexually-transmitted infections, and the cause of nearly all cervical and anogenital, and over half of oral cancers. Current HPV treatment is by lesion removal or through immunological intervention (imiquimod as an immune stimulant, or the HPV vaccines to prevent infection of the most common HPVs). While antiviral agents have been developed against many types of viruses, to date no true antivirals are available against HPV. With the heavy reliance on the immune system for HPV treatments/prevention, HPV infections and cancers remain a major problem for HIV/AIDS patients, even after HAART treatment. A true HPV antiviral that acts directly against HPV (and does not rely on the host immune system) would be an important weapon against HPV infections and cancers, particularly in HIV/AIDS patients. Recent successes of small molecule inhibitors that interfere with the herpesvirus primase-helicase interaction justify using such an approach against HPV. Our collaborator (Melendy, UB) has identified an interaction between the HPV DNA replication helicase, E1, and human Topoisomerase I that appears to be vital for HPV genome duplication. They will evaluate a panel of E1 mutations predicted to disrupt the interaction with Topoisomerase to more fully define this interaction. We will analyze the structure of this interaction by SAXS ( in collaboration with the Snell Lab) and single crystal complexes of the two proteins. These data will provide information that will be useful in developing second generation inhibitors that could act as potential HPV antiviral therapeutics.