Cervical cancer is one of the most frequent causes of cancer and death in women worldwide. Each year in the United States, 15,000 women develop cervical cancer and approximately 4,500 die from the disease. Cervical infection with human papillomaviruses (HPV) is the primary risk factor for cervical cancer. Cervical cancer has a long preclinical phase between HPV infection and invasive carcinoma that makes its prevention possible. My long-term goal is to understand the mechanisms by which HPV induces tumors and to develop preventive strategies for elimination of cervical cancer. HPV encodes a protein E6 that is essential for viral replication and HPV-induced cellular transformation. E6 is a multi-functional protein that performs its functions through interaction with cellular proteins. We have recently identified an alpha helical E6 binding domain that is conserved among E6-binding proteins. Our mutational analysis has identified amino acids within the consensus motif that are important for E6 binding. These amino acids and the three- dimensional structure of the E6-binding domain defined a first generation pharmacophore-the spatial distribution of the atoms needed to bind E6. We hypothesize that small molecules mimicking the pharmacophore will bind E6 and block the interaction of E6 with its cellular binding proteins and thus inhibit E6 biological activities that lead to the transformation of HPV-infected cells. We have used this structure-based drug design to select small molecules that could inhibit the interaction of E6 with its cellular partners. Our preliminary in vitro studies have identified multiple potential E6 inhibitors. In this proposal, we will describe experiments to further characterize these compounds.
Our specific aims are 1) In vitro specificity test for the potential E6 inhibitors; 2) To examine the ability of potential E6 inhibitors to disrupt biological activities of E6 in tissue culture assays. These studies may lead to the development of drugs to treat HPV infection and to prevent cervical cancer.
| Baleja, James D; Cherry, Jonathan J; Liu, Zhiguo et al. (2006) Identification of inhibitors to papillomavirus type 16 E6 protein based on three-dimensional structures of interacting proteins. Antiviral Res 72:49-59 |
| Liu, Yuqi; Liu, Zhiguo; Androphy, Elliot et al. (2004) Design and characterization of helical peptides that inhibit the E6 protein of papillomavirus. Biochemistry 43:7421-31 |
