TECHNOLOGY FOR THERAPEUTICS AGAINST CERVICAL CARCINOMA

大部分美国和全球人口（25-50%）感染了各种人乳头瘤病毒。高危型HPV与超过90%的宫颈癌和较小比例（10- 30%）的其他特定癌症相关。低风险HPV类型与常见疣有关。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。对于许多靶标，由于缺乏稳健的表型测定，标准药物筛选技术在开发治疗剂方面一直是无效的。拟议的研究通过初步筛选肽库作为小分子替代物来解决许多这些问题。作为DNA编码的分子引入，它们很容易使用标准分子生物学技术进行操作、分离和鉴定;可以快速筛选数百万种。更重要的是，它们利用了体细胞遗传学。因此，大量的肽可以在单个测定中进行集中测试;那些阻断表型选择的感兴趣的功能的肽被快速分离。这样的肽（干扰原）可以直接用于在标准生物化学（靶-干扰原）置换测定中筛选复杂的小分子文库。干扰素筛选方法可以极大地促进HPV相关疾病和其他疾病的药物开发。建议的商业应用：在美国，HPV感染的个体估计高达近50%。对于包括癌、良性病变和常见疣在内的宫颈肿瘤性病变的前期或后期，没有有效的非手术治疗方法。仅在美国，每年就有超过80亿美元用于异常子宫颈抹片检查的后续程序。HPV相关的健康风险不仅限于宫颈肿瘤，在全球范围内比例更高。两种HPV转化蛋白是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.