Developing Selective Inhibitors of GAPDHS and Sperm Glycolysis for Contraception

开发用于避孕的 GAPDHS 和精子糖酵解的选择性抑制剂

• 批准号: 8426181
• 负责人: Deborah A. O'Brien
• 金额: $ 21.3万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 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 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8426181
• 关键词: Address; Contraceptive Agents; Contraceptive methods; Development; Enzymes; Family Planning; Fertility; Germ Cells; Glyceraldehyde-3-Phosphate Dehydrogenases; Glycolysis; Goals; Health Planning; Human; Lead; Male Contraceptions; Male Contraceptive Agents; Metabolic Pathway; Mus; Pharmaceutical Chemistry; Pharmaceutical Preparations; Principal Investigator; Probability; Production; Protein Isoforms; Public Health; Recombinants; Research Personnel; Sperm Motility; Spermatogenic Cell; Structure-Activity Relationship; cell motility; cheminformatics; contraceptive target; design; drug discovery; high throughput screening; inhibitor/antagonist; male; men; novel; novel strategies; research study; screening; sperm cell; sperm function; tool; virtual

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.

描述（由申请方提供）：糖酵解对精子能量产生和活力至关重要。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型。这些新的异构体，特别是甘油醛3-磷酸脱氢酶-S（GAPDHS），是有前途的避孕目标，因为他们是特定的男性生殖细胞，精子活力和男性生育力，是必不可少的，非常适合药理学抑制。此外，我们的初步研究提供的证据表明，GAPDHS可以用小的药物样化合物进行差异抑制。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阻断精子糖酵解、ATP产生和运动。我们的目标是促进睾丸后非激素避孕药的开发，这种避孕药几乎没有直接阻碍精子功能的全身效应。具体目标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（特异性目标1）的化合物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 -分析经验证的命中化合物的结构-活性关系（SAR），以鉴定和开发作为GAPDHS的有效和选择性抑制剂的避孕先导物。 靶向精子特异性糖酵解酶代表了男性避孕的新方法。解决本提案目标的实验将由一个独特的研究人员团队进行，该团队具有使用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记录专业知识。这种能力的组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。 公众相关性：该提案的目标是开发一种直接阻断精子功能的安全有效的男性避孕药。为男子提供更好的避孕选择将促进全球公共卫生和计划生育工作。

项目成果

Recombinant human sperm-specific glyceraldehyde-3-phosphate dehydrogenase (GAPDHS) is expressed at high yield as an active homotetramer in baculovirus-infected insect cells.

• DOI: 10.1016/j.pep.2010.09.003
• 发表时间: 2011-01
• 期刊: PROTEIN EXPRESSION AND PURIFICATION
• 影响因子: 1.6
• 作者: Lamson, David R.;House, Alan J.;Danshina, Polina V.;Sexton, Jonathan Z.;Sanyang, Khaddijatou;O'Brien, Deborah A.;Yeh, Li-An;Williams, Kevin P.
• 通讯作者: Williams, Kevin P.

Development and Implementation of a High Throughput Screen for the Human Sperm-Specific Isoform of Glyceraldehyde 3-Phosphate Dehydrogenase (GAPDHS).

• DOI: 10.2174/1875397301105010030
• 发表时间: 2011
• 期刊: Current chemical genomics
• 作者: Sexton JZ;Danshina PV;Lamson DR;Hughes M;House AJ;Yeh LA;O'Brien DA;Williams KP
• 通讯作者: Williams KP