Deubiquitinating Enzymes as Targets for Male Contraception

去泛素化酶作为男性避孕的靶点

基本信息

批准号：
8909903
负责人：
CHRISTOPHER JESS PAYNE
金额：
$ 23.74万
依托单位：
LURIE CHILDREN'S HOSPITAL OF CHICAGO
依托单位国家：
美国
项目类别：
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/8909903
关键词：
Address Affect Animals Biological Assay Chemicals Computer Simulation Contraceptive Agents 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 Contraceptions Male Contraceptive Agents Male Infertility Mammalian Cell Measures Mus National Institute of Child Health and Human Development Nature Organ Peptide Hydrolases Pharmaceutical Chemistry Pregnancy Process Proteins Recycling Reproductive Biology Research Project Grants Specificity Sperm Motility Spermatids Spermatogenesis System Testis Ubiquitin Ubiquitin-Activating Enzymes Ubiquitin-Conjugating Enzymes Ubiquitin-Protein Ligase Complexes Vasectomy Vision Woman condoms contraceptive target field study in vivo inhibitor/antagonist loss of function male men mouse model multicatalytic endopeptidase complex novel overpopulation protein degradation public health relevance research study small molecule small molecule libraries sperm cell sperm function ubiquitin-protein ligase zygote

项目摘要

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（由适用提供）：该项目的核心目标是识别和表征泛素特异性肽51（USP51）的小分子抑制剂，一种非泛素化（DUB）酶的精子独家酶，是一种开发可逆性的，非激素的雄性抗抑制性的手段。泛素系统至关重要，以确保哺乳动物细胞内的蛋白质更新。泛素激活酶，泛素结合酶和泛素蛋白连接酶会催化泛素分子与蛋白质的附着，这一过程将它们靶向蛋白质组以降解。配音催化去除泛素以促进其回收。我们已经确定了USP51在晚期伸长的精子和附子精子中专门表达。由于精子运动的完整块，使用体内 - 多磷在小鼠中的USP51耗竭会导致男性不育症。我们的总体假设是TAT USP51是一个可行的避孕靶标，并且在自然界中存在的小分子或实验室中的修改将有效，可逆地抑制附睾精子中的USP51功能。我们将追求以下具体目的来解决这一假设：1）验证USP51作为避孕开发的有效策略。 2）筛选硅和体外中的小分子库，以鉴定命中化合物。 3）进行命中率对铅的药物化学优化和评估精子，测试和动物的暴露于候选者，以提高效率和可逆性。这些研究将提高我们对精子发生和精子功能的基本理解，并为开发新的避孕剂的潜力可逆地抑制关键的精子酶。