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Human papillomavirus (HPV) induces a variety of epithelial lesions of the skin and mucosa.While infection with high-risk HPV types may lead to the development of cervical cancer,low-riskHPV types cause warts.There is currently no medical cure for HPV infection.Although the prophylactic HPV vaccine has recently become available,it will not be effective for those who are already infected.We have taken multiple approaches to develop novel therapeutic treatment against HPV and HPV-associated lesions.We have previously identified a HPV oncogene E6-binding motif.Based on this finding,we performed a structure-based drug design to block HPV-associated malignant transformation.Compounds have been selected through computer based drug search from the NCI database that mimic the E6-binding motif and tested using in vitro and cell culture-based assays.Several compounds selectively inhibited E6 interaction with the E6-binding proteins E6AP and interfered with the ability of E6 to promote p53 degradation.Many of the chemotherapeutics use p53-induced apoptosis to kill cancer cells and will therefore not be effective in treating HPV-associated malignancies that have defective p53 pathway.Significantly,loss of p53 confers sensitization of tumor cells to certain DNA damaging and chemotherapeutic agents.We have explored this notion to enhance the efficacy of cervical cancer therapy.Using proteomic,genetic,pharmacologic,and siRNA strategies,we provide evidence that activation of cyclin-dependent kinase 1 (Cdkl or Cdc2) plays an important role in apoptosis in HPV-positive cells.In addition,we have demonstrated a tumor specific growth inhibition and apoptosis induction in cervical cancer cells by a plant extract.The mechanism by which the plant preparation induces cancer cell death has been explored.Furthermore,we are in the process of developing therapeutic HPV vaccines.These studies may lead to a novel approach to HPV-induced lesions.