HPV E6 Inhibitors for AIDS-Associated Malignancies

描述(申请人提供)：感染人乳头瘤病毒(HPV)与宫颈癌和肛门癌的发展密切相关，这两种癌症经常在艾滋病毒感染者中发现。目前还没有针对HPV感染的特效治疗方法。HPV疫苗如果成功，将不会对免疫抑制的个人有效。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诱发的癌症。HPVE6和E7蛋白对病毒复制和HPV诱导的细胞转化是必不可少的。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，该基序在几个E6结合蛋白中保守。我们已经确定了包含该基序的多肽的结构，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，呈现药效团的小分子将与E6结合，阻止其与细胞蛋白的相互作用，从而诱导细胞凋亡。我们已经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适度效力的特定抑制E6活性的化合物。在这项建议中，我们将(1)基于药效团和活性化合物合成化学库，并使用我们新开发的编码组合化学合成技术筛选与E6结合的化合物库；(2)测试从化学优化获得的HITS的特异性和有效性。我们希望找到能够显著提高药效的特定抑制E6功能的化合物。这些研究将导致开发治疗HPV感染和HIV感染患者的HPV相关癌症的药物。

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.