HPV E6 Inhibitors for AIDS-Associated Malignancies

描述（由申请人提供）：人乳头瘤病毒（HPV）感染与宫颈癌和肛门生殖器癌的发展密切相关，这两种癌症常见于艾滋病毒感染者。目前尚无针对HPV感染的特异性和有效的治疗方法。HPV疫苗即使成功，对免疫抑制的个体也无效。我们的长期目标是为消除艾滋病患者的HPV感染和HPV诱导的癌症制定治疗策略。HPV E6和E7蛋白是病毒复制和HPV诱导的细胞转化所必需的。E6抑制e7诱导的细胞凋亡。E6通过与肿瘤抑制因子p53和其他细胞蛋白相互作用来发挥其功能。我们计划以E6为靶点进行抑制。为了实现这一目标，我们已经确定了一个E6结合基序，它在几个E6结合蛋白中是保守的。我们已经确定了含有该基序的肽的结构，并确定了对E6结合很重要的氨基酸。这些氨基酸和E6结合域的结构定义了一个药效团——结合E6所需原子的空间分布。我们假设呈现药效团的小分子会结合E6并阻断其与细胞蛋白的相互作用，从而诱导细胞凋亡。我们选择了一组存在药效团的化合物，并在体外鉴定了几种具有中等效力的特异性抑制E6活性的化合物。在本课题中，我们将(1)基于药效团和活性化合物合成化学文库，并利用我们新开发的编码组合化学合成技术筛选与E6结合的化合物；(2)对化学优化得到的hit进行特异性和效价测试。我们期望找到特异性抑制E6功能的化合物，并大大提高其效力。这些研究将导致治疗hiv感染患者的HPV感染和HPV相关癌症的药物的开发。

DESCRIPTION (provided by applicant): Infection with human papillomaviruses (HPV) is strongly associated with the development of cervical and anogenital cancers, which are frequently found in HIV-infected individuals. Specific and effective therapies for HPV infection are not available. A HPV vaccine, if successful, will not be effective in immunosuppressed individuals. Our long-term goal is to develop therapeutic strategies for elimination of HPV infection and HPV-induced cancers in people with AIDS. The HPV E6 and E7 proteins are essential for viral replication and HPV-induced cellular transformation. E6 inhibits E7-induced apoptosis. E6 performs its functions through interaction with the tumor suppressor p53 and other cellular proteins. We plan to target E6 for inhibition. To achieve this goal, we have identified an E6 binding motif that is conserved among several E6-binding proteins. We have determined the structure of peptides containing this motif and identified amino acids that are important for E6 binding. These amino acids and the structure of the E6-binding domain defined a pharmacophore-the spatial distribution of the atoms needed to bind E6. We hypothesize that small molecules presenting the pharmacophore will bind E6 and block its interaction with cellular proteins and thus induce apoptosis. We have selected a set of compounds for presence of the pharmacophore and identified several compounds that specifically inhibited E6 activities with modest potency in vitro. In this proposal, we will (1) synthesize chemical libraries based on the pharmacophore and the active compounds and screen the library for compounds that bind E6 using our newly developed encoding combinatorial chemical synthesis technology; and (2) test the specificity and potency of the hits obtained from chemical optimization. We expect to identify compounds that specifically inhibit E6 functions with greatly improved potency. These studies will lead to the development of drugs to treat HPV infection and HPV-associated cancers in HIV-infected patients.