identification of small molecule contraceptives that target the male germline

鉴定针对男性种系的小分子避孕药

• 批准号: 8064005
• 负责人: MARTIN M. MATZUK
• 金额: $ 24.29万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-02-15 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8064005
• 关键词: American; Binding; Bioinformatics; Biological Assay; Chemicals; Clinical Trials; Contraceptive Agents; Contraceptive methods; Development; Drug Antagonism; Evaluation; Genes; Goals; Healthy People 2010; Histology; Hybrids; In Vitro; Knock-out; Laboratories; Lead; Libraries; Male Contraceptive Agents; Marketing; Methods; Mus; Oral; Oral Contraceptives; Pathway interactions; Pharmaceutical Preparations; Population; Principal Investigator; Process; Proteins; Public Health; Research Proposals; Scientist; Screening procedure; Sperm Count Procedure; Spermatids; Spermatocytes; Spermatogenesis; Sterility; Structure; Teenagers; Testing; Woman; analog; contraceptive target; cost; in vivo; male; men; multidisciplinary; nonhuman primate; novel; pill; protein complex; protein protein interaction; protein structure; research and development; research study; small molecule; unintended pregnancy

DESCRIPTION (provided by applicant): Since the development of the birth control pill for women, the past several decades have seen few advances in contraception. Furthermore, there is still no effective oral contraceptive pill for men. As stated in Healthy People 2010, "contraceptive research and development efforts must be expanded to bring new methods to the market." Thus, we need more effective, inexpensive, long-acting, and easily administered contraceptives, especially for men. In this proposal, we will focus on four intriguing and evolutionarily-conserved proteins that we hypothesize are outstanding targets for novel contraceptives. Knockout studies have demonstrated that mice lacking GASZ, VASA, TEX14, and STYX have a block at different points in spermatogenesis ranging from spermatocytes to spermatids, resulting in sterility. With the aid of our collaborators, Drs. Angela Koehler, Peter Davies, and Laising Yen, the overall goal of this research proposal from the Matzuk laboratory is to identify small molecules and chemical analogs that bind to these spermatogenic-specific proteins to block their function and/or disrupt protein:protein complexes, thereby causing a contraceptive effect. Our overall hypothesis is that we will rapidly identify multiple lead compounds that are directed at these unique and essential spermatogenic proteins and can be used to synthesize an assortment of oral and implantable contraceptives for men. The Specific Aims of these proposed U01 studies are: 1) Use small molecule microarrays and 2-hybrid screening assays to identify small molecules that bind GASZ, VASA, TEX14, or STYX and/or block key protein:protein interactions; and 2) Perform in vitro, in vivo, and computational screens to identify the most promising male contraceptives. Our studies are the first of their kind to use small molecule microarrays and mammalian 2-hybrid screening assays to identify small molecules that can act as contraceptives. We have put together a strong multidisciplinary group of scientists to tackle this important public health problem, and as a result, we believe that we can generate several novel contraceptives that will target unique proteins, structures, and processes in the germline in men. PUBLIC RELEVANCE: Despite the rapid increase in the world's population, the high rate of unintended pregnancies in U.S. teenagers (1 million per year), and the staggering cost to the American taxpayer of these unintended pregnancies ($7-$15 billion per year), there is no oral contraceptive for men. This application will focus on the identification of small molecules that target the male germline. Our studies are unique since they will use small molecule microarrays and protein:protein interaction assays to identify and characterize drugs that cause their contraceptive effect by inhibiting specific structures or pathways during spermatogenesis.

描述（由申请人提供）： 自从女性避孕药问世以来，在过去的几十年里，避孕方面几乎没有什么进展。此外，仍然没有有效的男性口服避孕药。正如《2010年健康人民》所指出的，“必须扩大避孕研究和开发工作，将新方法推向市场。“因此，我们需要更有效、更便宜、更长效、更容易管理的避孕药具，特别是对男性而言。在这个建议中，我们将集中在四个有趣的和进化上保守的蛋白质，我们假设是新的避孕药的突出目标。基因敲除研究表明，缺乏GASZ，VASA，TEX 14和STYX的小鼠在精子发生的不同点（从精母细胞到精子细胞）都有阻滞，导致不育。在我们的合作者安吉拉博士的帮助下 Koehler，Peter Davies和Laising Yen，Matzuk实验室这项研究提案的总体目标是鉴定与这些精子发生特异性蛋白质结合的小分子和化学类似物，以阻断其功能和/或破坏蛋白质：蛋白质复合物，从而产生避孕效果。我们的总体假设是，我们将快速识别针对这些独特和必需的生精蛋白的多种先导化合物，并可用于合成各种口服和植入式男性避孕药。这些U 01研究的具体目的是：1）使用小分子微阵列和双杂交筛选试验来鉴定结合GASZ、VASA、TEX 14或STYX和/或阻断关键蛋白质：蛋白质相互作用的小分子; 2）进行体外、体内和计算筛选，以鉴定最有前途的男性避孕药。我们的研究是第一次使用小分子微阵列和哺乳动物双杂交筛选试验来鉴定可以作为避孕药的小分子。我们已经组建了一个强大的多学科科学家小组来解决这一重要的公共卫生问题，因此，我们相信我们可以产生几种新型避孕药，这些避孕药将针对男性生殖细胞中的独特蛋白质，结构和过程。 公众相关性：尽管世界人口迅速增长，美国青少年意外怀孕率很高（每年100万），这些意外怀孕给美国纳税人带来了惊人的成本（每年70 - 150亿美元），但没有男性口服避孕药。该应用将集中于鉴定靶向雄性生殖系的小分子。我们的研究是独一无二的，因为他们将使用小分子微阵列和蛋白质：蛋白质相互作用测定，以确定和表征药物，通过抑制精子发生过程中的特定结构或途径，导致其避孕效果。