Developing Selective Inhibitors of GAPDHS and Sperm Glycolysis for Contraception

描述（由申请人提供）：糖酵解是精子能量产生和运动所必需的。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发现的同种异构体。这些新的异构体，特别是甘油醛3-磷酸脱氢酶s (GAPDHS)，是很有希望的避孕靶点，因为它们是男性生殖细胞特异性的，对精子活力和男性生育能力至关重要，并且非常适合药物抑制。此外，我们的初步研究提供了证据，证明GAPDHS可以被小的药物样化合物不同程度地抑制。本提案的目的是鉴定和验证选择性抑制GAPDHS的先导化合物，并确定这些化合物是否特异性地阻断精子糖酵解、ATP产生和运动。我们的目标是促进一种睾丸后、非激素避孕药的发展，这种避孕药几乎没有直接阻碍精子功能的系统性影响。特异性目标1 -使用高通量筛选（HTS）和虚拟筛选方法来鉴定选择性抑制人GAPDHS的命中化合物。特异性目标2 -确定抑制重组GAPDHS的化合物（特异性目标1）是否也抑制小鼠和人类精子中的GAPDHS活性、ATP产生和运动性。具体目标3 -分析已验证的命中化合物的构效关系（SAR），以确定和开发有效的选择性GAPDHS抑制剂的避孕先导物。针对精子特异性糖酵解酶是一种新的男性避孕方法。针对本提案目标的实验将由一个独特的研究团队进行，他们在使用药物发现工具（如HTS、药物化学和化学信息学）分析精子功能和抑制剂设计方面具有文献记载的专业知识。这种能力的结合有望产生有价值的新信息，很有可能导致开发一种新的男性专用避孕药具。

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.