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生密切相关，这些癌常见于HIV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，如果成功的话，将不会对免疫抑制的个体有效。我们的长期目标是开发治疗策略，以消除艾滋病患者的HPV感染和HPV诱导的癌症。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为目标进行抑制。为了实现这一目标，我们已经确定了一个E6结合基序，是保守的几个E6结合蛋白。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，小分子的药效团将结合E6和阻断其与细胞蛋白质的相互作用，从而诱导细胞凋亡。我们已经选择了一组化合物的药效团的存在，并确定了几种化合物，特异性抑制E6的活动，在体外具有适度的效力。在这个提议中，我们将（1）基于药效团和活性化合物合成化学文库，并使用我们新开发的编码组合化学合成技术筛选结合E6的化合物库;（2）测试从化学优化获得的命中的特异性和效力。我们期望鉴定出特异性抑制E6功能的化合物，其效力大大提高。这些研究将导致开发药物来治疗HIV感染患者的HPV感染和HPV相关癌症。

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.