Deubiquitinating Enzymes as Targets for Male Contraception

去泛素化酶作为男性避孕的靶点

• 批准号: 9253031
• 负责人: CHRISTOPHER JESS PAYNE
• 金额: $ 22.71万
• 依托单位: LURIE CHILDREN'S HOSPITAL OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9253031
• 关键词: Address; Animals; Biological Assay; Chemicals; Computer Simulation; Contraceptive Agents; Contraceptive Availability; Country; Deubiquitinating Enzyme; Development; Drug Targeting; Ensure; Enzymes; Epididymis; Excision; Experimental Designs; Failure; Female; Fertility; Fertilization; Funding Opportunities; Generations; Goals; Hormonal; In Vitro; Knockout Mice; Laboratories; Lead; Male Contraceptive Agents; Male Infertility; Mammalian Cell; Measures; Mus; National Institute of Child Health and Human Development; Nature; Peptide Hydrolases; Pharmaceutical Chemistry; Phenotype; Pregnancy; Process; Proteins; Recycling; Reproductive Biology; Research Project Grants; Specificity; Sperm Motility; Spermatids; Spermatogenesis; System; Testis; Ubiquitin; Ubiquitin-Activating Enzymes; Ubiquitin-Conjugating Enzymes; Vasectomy; Vision; Woman; condoms; contraceptive target; experimental study; in vivo; loss of function; male; men; mouse model; multicatalytic endopeptidase complex; novel; overpopulation; protein degradation; public health relevance; small molecule; small molecule inhibitor; small molecule libraries; sperm cell; sperm function; ubiquitin-protein ligase; zygote

 DESCRIPTION (provided by applicant): The central goal of this project is to identify and characterize small molecule inhibitors of Ubiquitin specific peptidase 51 (USP51), a deubiquitinating (DUB) enzyme exclusive to sperm, as a means to develop a reversible, non-hormonal male contraceptive. The ubiquitin system is fundamental to ensure protein turnover within mammalian cells. Ubiquitin-activating enzymes, ubiquitin-conjugating enzymes, and ubiquitin protein ligases catalyze the attachment of ubiquitin molecules to proteins, a process that targets them to the proteasome for degradation. DUBs catalyze the removal of ubiquitin to facilitate their recycling. We have identified USP51 to be specifically expressed in late elongating spermatids and epididymal sperm. USP51 depletion in mice using Vivo-Morpholinos results in male infertility due to a complete block of sperm motility. Our overall hypothesis is tat USP51 is a viable contraceptive target and that small molecules existing in nature or modified in the laboratory will effectively and reversibly inhibit USP51 function in epididymal sperm. We will pursue the following Specific Aims to address this hypothesis: 1) Validate the targeting of USP51 as an effective strategy for contraceptive development. 2) Screen small molecule libraries in silico and in vitro to identify hit compounds. 3) Perform hit-to-lead medicinal chemistry optimization and assess the exposure of sperm, testes and animals to candidates for efficacy and reversibility. These studies will advance our basic understanding of spermatogenesis and sperm function, as well as provide the potential for developing new contraceptive agents that reversibly inhibit a critical sperm enzyme.

 描述（由申请人提供）：该项目的中心目标是鉴定和表征泛素特异性肽酶 51 (USP51) 的小分子抑制剂，泛素特异性肽酶 51 是一种精子独有的去泛素化 (DUB) 酶，作为开发可逆、非激素男性避孕药的一种手段。泛素系统对于确保哺乳动物细胞内的蛋白质周转至关重要。泛素激活酶、泛素结合酶和泛素蛋白连接酶催化泛素分子与蛋白质的附着，这一过程将蛋白质靶向蛋白酶体进行降解。 DUB 催化泛素的去除，以促进其回收。我们已经确定USP51在晚期伸长精子细胞和附睾精子中特异性表达。使用 Vivo-Morpholinos 去除小鼠体内的 USP51 会导致精子活力完全受阻，从而导致男性不育。 我们的总体假设是 USP51 是一个可行的避孕靶标，自然界中存在的或实验室修饰的小分子将有效且可逆地抑制附睾精子中的 USP51 功能。我们将追求以下具体目标来解决这一假设：1) 验证 USP51 的目标作为避孕药具开发的有效策略。 2) 在计算机和体外筛选小分子库以鉴定命中化合物。 3) 执行从命中到先导的药物化学优化，并评估精子、睾丸和动物与候选药物的接触情况，以了解其功效和可逆性。这些研究将增进我们对精子发生和精子功能的基本了解，并为开发可逆地抑制关键精子酶的新型避孕药提供潜力。