Large proportions of the US and global populations (25-50%) are infected with a variety of human papilloma viruses. High-risk HPV types are associated with over 90% of cervical carcinomas and smaller proportions (10- 30%) of other specific carcinomas. Low-risk HPV types are associated with common warts. Two gene products, E6 and E7, are primarily responsible for HPV-related cellular transformation. These proteins are ideal targets for therapeutic intervention. However, there are currently no effective therapeutic treatments. For many targets, standard drug screening technologies have been ineffective in developing therapeutics due to the lack of robust phenotypic assays. The proposed research alleviates a number of these problems by initially screening peptide libraries as small molecule-surrogates. Introduced as DNA-encoded molecules they are easily manipulated, isolated and identified using standard molecular biological techniques; millions can be rapidly screened. More importantly, they leverage the use of somatic cell genetics. Thus, a large collection of peptides can be tested en masse in a single assay; those blocking phenotypically selected functions of interest are rapidly isolated. Such peptides (perturbagens) can be used directly to screen complex small molecule libraries in standard biochemical (target- perturbagen) displacement assays. Perturbagen screening methods may greatly facilitate drug development for HPV-related and other diseases.
Estimates of HPV-infected individuals in the US range up to nearly 50%. There are no effective nonsurgical therapeutic approaches to treat the precursors or later stages of cervical neoplastic lesions including carcinoma, benign lesions and common warts. Over $8 billion is spent annually on follow-up procedures for aberrant PAP smears in the US alone. HPV-related heath risks are not restricted to cervical neoplasias and globally are proportionately even greater. Two HPV transforming proteins are ideal candidate target proteins for specific therapeutic intervention.
