identification of small molecule contraceptives that target the male germline

描述(申请人提供)：自从为女性开发避孕药以来，在过去的几十年里，避孕方面几乎没有什么进步。此外，目前仍没有有效的男性口服避孕药。正如《2010年健康人》中所述，“必须加大避孕研究和开发力度，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，尤其是对男性来说。在这项提案中，我们将重点关注四种耐人寻味的、进化上保守的蛋白质，我们假设它们是新型避孕药物的杰出靶点。基因敲除研究表明，缺乏GASZ、VASA、TEX14和STYX的小鼠在从精母细胞到精子细胞的不同精子发生点上都有障碍，导致不育。在我们合作者的帮助下，安吉拉博士 Koehler，Peter Davies和Laising Yen，Matzuk实验室这项研究提案的总体目标是识别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，以阻断它们的功能和/或破坏蛋白质：蛋白质复合体，从而产生避孕效果。我们的总体假设是，我们将迅速确定多种先导化合物，这些先导化合物针对这些独特和必要的生精蛋白，可用于合成各种男性口服和植入型避孕药。这些建议的U01研究的具体目标是：1)使用小分子微阵列和双杂交筛选分析来确定与GASZ、VASA、TEX14或STYX结合的小分子和/或阻断关键蛋白质：蛋白质相互作用；以及2)进行体外、体内和计算机筛选，以确定最有希望的男性避孕药。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识别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，我们相信我们可以生产出几种针对男性生殖线中独特的蛋白质、结构和过程的新型避孕药。 公共关系：尽管世界人口迅速增长，美国青少年意外怀孕的比率很高(每年100万美元)，这些意外怀孕给美国纳税人带来了惊人的成本(每年70亿至150亿美元)，但男性没有口服避孕药。这项应用将专注于识别以雄性生殖系为目标的小分子。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：蛋白质相互作用分析来识别和表征通过抑制精子发生期间的特定结构或途径而产生避孕效果的药物。

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.