Developing Selective Inhibitors of GAPDHS and Sperm Glycolysis for Contraception

描述(申请人提供)：糖酵解对精子的能量产生和活力是必不可少的。这一中心代谢途径中的几种酶具有仅在发育中的生精细胞和成熟精子中存在的异构体。这些新的异构体，特别是3-磷酸甘油醛脱氢酶-S(GAPDHS)，是很有希望的避孕靶点，因为它们是男性生殖细胞所特有的，对精子运动和男性生育是必不可少的，并且非常适合于药物抑制。此外，我们的初步研究提供了证据，证明GAPDHS可以与小的类药物化合物区别地抑制。该提案的目的是识别和验证选择性抑制GAPDHS的先导化合物，并确定这些化合物是否专门阻止精子糖酵解、ATP产生和运动。我们的目标是促进一种睾丸后、非激素避孕药的开发，这种避孕药几乎不会产生直接阻止精子功能的全身影响。具体目标1-使用高通量筛选(HTS)和虚拟筛选方法来识别选择性抑制人类GAPDHS的HIT化合物。特定目的2-确定抑制重组GAPDHS的化合物(特定目的1)是否也抑制小鼠和人类精子的GAPDHS活性、ATP生成和活力。具体目标3-分析有效的HIT化合物的结构-活性关系(SAR)，以确定和开发作为GAPDHS的有效和选择性抑制剂的避孕先导。靶向精子特异性糖酵解酶代表了一种新的男性避孕方法。针对这项提案目标的实验将由一个独特的调查团队进行，该团队拥有利用HTS、药物化学和化学信息学等药物发现工具分析精子功能和抑制剂设计的有据可查的专业知识。这种能力的结合有望产生有价值的新信息，极有可能导致新型男性专用避孕药的开发。 与公众相关：这项提案的目标是开发一种安全有效的男性避孕药，直接阻止精子功能。为男性提供更好的避孕选择将促进全球公共卫生和计划生育努力。

DESCRIPTION (provided by applicant): Glycolysis is essential for sperm energy production and motility. Several enzymes in this central metabolic pathway have isoforms that are only found in developing spermatogenic cells and mature sperm. These novel isoforms, particularly glyceraldehyde 3-phosphate dehydrogenase-S (GAPDHS), are promising contraceptive targets because they are specific to male germ cells, essential for sperm motility and male fertility, and are well suited to pharmacological inhibition. Furthermore, our preliminary studies provide evidence that GAPDHS can be differentially inhibited with small, drug-like compounds. The objectives of this proposal are to identify and validate lead compounds that selectively inhibit GAPDHS and to determine if these compounds specifically block sperm glycolysis, ATP production and motility. Our goal is to facilitate the development of a post-testicular, non-hormonal contraceptive with little potential for systemic effects that directly blocks sperm function. Specific Aim 1 - Use high throughput screening (HTS) and virtual screening approaches to identify hit compounds that selectively inhibit human GAPDHS. Specific Aim 2 - Determine if compounds that inhibit recombinant GAPDHS (Specific Aim 1) also inhibit GAPDHS activity, ATP production and motility in mouse and human sperm. Specific Aim 3 - Analyze structure-activity relationships (SAR) of validated hit compounds to identify and develop contraceptive leads that are potent and selective inhibitors of GAPDHS. Targeting sperm-specific glycolytic enzymes represents a novel approach to male contraception. Experiments addressing the aims of this proposal will be performed by a unique team of investigators with documented expertise in the analysis of sperm function and inhibitor design using drug discovery tools such as HTS, medicinal chemistry and cheminformatics. This combination of capabilities promises to yield valuable new information with a high probability of leading to the development of a novel male-specific contraceptive. PUBLIC RELEVANCE: The goal of this proposal is to develop a safe and effective male contraceptive that directly blocks sperm function. The availability of better contraceptive options for men would facilitate global public health and family planning efforts.