TECHNOLOGY FOR THERAPEUTICS AGAINST CERVICAL CARCINOMA

很大比例的美国和全球人口(25%-50%)感染了各种人类乳头状瘤病毒。高危HPV类型与90%以上的宫颈癌和较小比例(10%-30%)的其他特定癌症有关。低风险的HPV类型与常见的疣有关。两种基因产物E6和E7主要负责HPV相关的细胞转化。这些蛋白质是治疗干预的理想靶点。然而，目前还没有有效的治疗方法。对于许多靶点来说，由于缺乏可靠的表型分析，标准的药物筛选技术在开发治疗方面已经无效。这项拟议的研究通过初步筛选作为小分子替代品的肽库，缓解了许多这样的问题。它们被引入为DNA编码的分子，使用标准的分子生物学技术很容易操作、分离和鉴定；可以快速筛选数百万人。更重要的是，它们利用了体细胞遗传学。因此，可以在一次测试中整体测试大量的多肽；那些阻断感兴趣的表型所选功能的多肽被快速分离出来。这种多肽(微扰剂)可直接用于在标准生化(靶-微扰剂)置换分析中筛选复杂的小分子文库。Perturgen筛查方法可能极大地促进HPV相关疾病和其他疾病的药物开发。建议的商业应用：据估计，美国HPV感染者的比例高达近50%。目前还没有有效的非手术治疗方法来治疗宫颈肿瘤的前期或晚期病变，包括癌、良性病变和常见的尖锐湿疣。仅在美国，每年就有超过80亿美元用于异常宫颈涂片的后续程序。与HPV相关的健康风险并不局限于宫颈肿瘤，从比例上讲，全球的风险更大。两种HPV转化蛋白是进行特异性治疗干预的理想候选靶蛋白。

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. PROPOSED COMMERCIAL APPLICATIONS: 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.