Abstract 1.

Introduction: Cervical cancer will kill

several hundred thousand women around the world during the next few years. It ranks second only to breast cancer as the leading cause of cancer death in women worldwide. Every year, approximately 470,000 new cases of cervical cancer are diagnosed and approximately 230,000 women worldwide die of the disease, with the majority (~80%) of these cases and deaths occurring in developing countries.

Human papillomaviruses (HPVs) are the etiological agents in nearly all cases (99.7%) of cervical cancer (1,2). HPV genomes encode proteins with molecular properties required for cellular transformation in cell culture and in situ (35). HPV16 is the most common HPV type in malignant neoplasia and is found in about 60% of all cervical carcinomas, while about 20 other HPV types account for another 30% of these malignancies (35). However, other HPV types are most often associated with benign neoplasia, such as genital warts. The genital HPV types are sexually transmitted and can be further divided into low-risk and highrisk groups according to the propensity of their induced lesions to progress to malignancy. The low-risk HPV types, such as types 6 and 11, are associated with genital warts that do not progress toward cancer, while the high-risk HPV types cause intraepithelial lesions that can progress to invasive carcinomas [5]. Specifically, HPV16 and HPV18 are the high-risk types most frequently associated with cervical squamous cell carcinomas (50% and 20%, respectively). High-risk HPV types are also associated with approximately 25% of head and neck carcinomas (of the mouth, tonsils, esophagus and larynx, in particular) [6,7]. Infection by HPV16 can persist subclinically or can develop into potential precursor lesions of cervical cancer, which are called cervical intraepithelial neoplasia or squamous intraepithelial lesions (8). These lesions can regress or progress to invasive cancer, likely as a result of the acquisition of additional mutations in cellular genes as a consequence of HPV gene functions (9,10). Current treatment for HPV16-associated lesions is surgery, while limited success is achieved with immune modulators like interferon against HPV6- and HPV11- associated lesions. Prevention of HPV infection by vaccination and challenge of established HPV infections by immune therapy are under investigation but not yet established. and observing the mortality rate one has to conclude that treatment of these virally caused neoplasias is still inadequate in spite of the long-term establishment of surgical techniques.These statistics suggest a need for alternatives to current treatment approaches. With the detailed knowledge of the molecular biology of HPVs, it is now possible to target individual HPV proteins by chemical compounds that interfere selectively with the tertiary structure and function of viral gene products. Thus Compounds with desirable properties designed in silico and tested in vitro may lead to the development of drugs to treat HPV infection or HPVassociated neoplasia in situ. HPVs have circular, double-stranded DNA genomes that are approximately 8 kilobases in size and encode eight genes that are homologous among all genital HPV types. The transforming properties of HPV16 originate from three oncoproteins that are the products of the E5, E6, and E7 genes. These proteins have pleiotropic effects with consequences for transmembrane signaling, regulation of the cell cycle, transformation of established cell lines, immortalization of primary cell lines, and chromosomal stability (3,4). The E6 oncoprotein can form a ternary complex with the cell-cycle regulator p53 and the E6-associated protein E6AP (Fig.1), resulting in degradation of p53 by the ubiquitination pathway (11,12). E6 can also bind E6-binding protein (E6BP; also known as ERC-55), a calciumbinding protein localized in the endoplasmic reticulum, with possible consequences for