HPV E6 Inhibitors for AIDS-Associated Malignancies

HPV E6 抑制剂治疗艾滋病相关恶性肿瘤

• 批准号: 6799495
• 负责人: JASON J CHEN
• 金额: $ 21.8万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-05-01 至 2006-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6799495
• 关键词: AIDS related neoplasm /cancer; antiviral agents; apoptosis; binding proteins; chemical synthesis; combinatorial chemistry; drug discovery /isolation; drug receptors; human papillomavirus; inhibitor /antagonist; molecular site; virus protein; AIDS related neoplasm /cancer; antiviral agents; apoptosis; binding proteins; chemical synthesis; combinatorial chemistry; drug discovery /isolation; drug receptors; human papillomavirus; inhibitor /antagonist; molecular site; virus protein

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.

描述（由申请人提供）：人类乳头瘤病毒（HPV）的感染与宫颈和肛门生殖器癌的发展密切相关，这些癌症经常在HIV感染的个体中发现。没有可用于HPV感染的特定有效疗法。如果成功的话，HPV疫苗将在免疫抑制的个体中无效。我们的长期目标是制定消除患有艾滋病患者的HPV感染和HPV引起的癌症的治疗策略。 HPV E6和E7蛋白对于病毒复制和HPV诱导的细胞转化至关重要。 E6抑制E7诱导的凋亡。 E6通过与肿瘤抑制p53和其他细胞蛋白的相互作用来执行其功能。我们计划针对E6进行抑制。为了实现这一目标，我们已经确定了在几种E6结合蛋白中保守的E6结合基序。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结合结构域的结构定义了结合E6所需的原子的空间分布。我们假设呈现药效团的小分子将结合E6并阻止其与细胞蛋白的相互作用，从而诱导凋亡。我们已经选择了一组化合物来存在药效团，并鉴定了几种化合物，这些化合物专门抑制了E6活性，并具有适度的体外效力。在此提案中，我们将（1）根据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化学合成技术筛选了库的化合物； （2）测试从化学优化获得的点击的特异性和效力。我们希望鉴定出具有大大提高效力的E6功能的化合物。这些研究将导致在HIV感染患者中治疗HPV感染和与HPV相关的癌症的药物开发。