This project will identify imidazole-pyrrole polyamides to be used as topical antiviral agents for the treatment of human papillomavirus (HPV). Current treatments, which include surgery, freezing, noxious agents, and "biological response modifiers" are primitive or non-specific. We hypothesize that several compounds with antiviral activity will be found among a library of imidazole-pyrrole polyamides targeting the HPV18 E1 binding site similar to our preliminary studies with HPV16 and HPV31. This Phase 1 study will establish a keratinocyte culture system that supports HPV18 episomal maintenance. Polyamides will be synthesized that target the HPV18 origin of replication (ori), and tested for their ability to suppress episomal DNA levels. Active compounds will then be tested in assays designed to confirm specificity and to establish baseline selectivity indices. To meet these objectives, the following specific aims will be pursued: Aim 1: Chemistry. The viral origin of replication (ori) for HPV18 will be targeted by synthesis of a series of polyamides designed to recognize the specific sequence of the HPV18 E1 binding site. Aim 2: The effects of polyamides on HPV18 replication and maintenance will be tested in cell culture. Aim 3: Compounds that produce a decrease in HPV18 DNA levels will be further characterized, conditions will be established for maximum antiviral effects in cell culture, and initial in vitro toxicity assessments will be conducted. Successful completion of these studies offers the promise of specific antiviral treatments for HPV. It is anticipated that compounds reducing viral DNA load will by themselves, or in conjunction with the host immune system in vivo, be ultimately sufficient to clear cells infected with HPV. These studies are important because they provide an alternative to the vaccine approaches to HPV which have come to dominate the pharmaceutical industry, while offering no hope to those people currently or soon to be infected with the virus. In addition, these studies may identify valuable research tools for use in understanding important aspects of the HPV life cycle. Future Phase 2 studies will test the efficacy of active compounds in complex cell culture models (raft cultures) and animal models of HPV-related disease. In addition, bioavailability studies will focus on developing optimal topical treatment formulations and upon measuring systemic exposure following topical treatments. These studies will be required to guide toxicological studies prior to testing in humans. Ultimately, the project seeks to use polyamides targeting one of the most prevalent cancer causing viruses (HPV18) as topical agents in a clinical setting. Human papillomavirus is the leading cause of cervical cancer, which is second only to breast cancer as a killer of women. There are currently no specific antiviral treatments for HPV. The studies described here are designed to identify agents that will be used as topical antiviral treatment s for HPV 18, one of the most important cancer-causing viruses.
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