Targeting the MEIG1/PACRG interaction for male contraception.

针对男性避孕的 MEIG1/PACRG 相互作用。

• 批准号: 10527627
• 负责人: Zhibing Zhang
• 金额: $ 23.1万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-20 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10527627
• 关键词: Affinity; Amino Acids; Animals; Artificial Intelligence; Binding; Biochemical; Biological Assay; Cell Communication; Cells; Collaborations; Complement; Complex; Contraceptive Agents; Couples; Crystallization; Data; Databases; Development; Drug usage; Female Contraceptive Agents; Future; Gene Structure; General Population; Genes; Genetic; Goals; Hormone use; Human; Interruption; Investigational New Drug Application; Knockout Mice; Lead; Libraries; Ligands; Luciferases; Male Contraceptive Agents; Male Infertility; Mediating; Meiosis; Methods; Microtubules; Mus; Muscular Atrophy; Parkin; Performance; Pharmaceutical Preparations; Phenotype; Point Mutation; Production; Proteins; Societies; Spermatids; Spermatocytes; Spermatogenesis; Structure; Techniques; Technology; Testing; Testosterone; Validation; Vasectomy; Withdrawal; base; birth control; condoms; drug development; gene interaction; genetic testing; in silico; male; muscle form; mutant; novel; pill; reversible contraceptive; screening; side effect; small molecule; small molecule libraries; sperm cell; unintended pregnancy; virtual

Summary Development of male contraceptives has lagged far behind that of female contraceptives. Current physical options for male birth control have limitations with respect to reliability, consistency of use, and invasiveness, respectively. Inhibiting sperm production by decreasing testosterone levels would also cause unacceptable side effects. Thus, our long-term objective is to develop a contraceptive that blocks the late stage of spermatogenesis without the use of hormones so that the effect is reversible with fewer/no side effects. The manchette is a transient microtubule-containing structure that is present only in elongating spermatids, and genetic disruption of the manchette structure/function results in male infertility. Importantly, we have discovered that the function of the machete in spermatogenesis requires the interaction between meiosis expressed gene 1 (MEIG1) and Parkin co-regulated gene (PACRG). A single point mutation in MEIG1 or PACRG that disrupts the interaction of the two proteins also disrupts spermatogenesis resulting in pure male infertility. Interaction between MEIG1 and PACRG is conserved in humans. We hypothesize that compounds that disrupt the MEIG1/PACRG interaction can be developed into safer and effective male contraceptives. Availability of the MEIG1/PACRG structure makes it possible to in silico virtual and artificial intelligence (AI) screens for small molecules that block MEIG1/PACRG interaction, with biochemical validation hits. Thus, the objective of the present application is to conduct in silico virtual and AI screens to identify small molecules that block the interaction of MEIG1 and PACRG which can be developed into leads for male contraceptives. To this end, we provide preliminary data for a robust G. princeps luciferase complementation assay for the interaction of MEIG1 and PACRG that can be readily used to validate the effect of the small molecules identified from the virtual and AI screens. In addition, a fragment library for compounds is available for a physical screen and the fragments that interrupt MEIG1/PACRG interaction can also be used for drug development in the future. Thus, we propose the following two aims: 1: To complete the in silico virtual screen and to examine the effect of small molecules identified by the in silico virtual and AI screens on interrupting MEIG1/PACRG interaction; 2: To screen a fragment library for compounds that disrupt the MEIG1/PACRG interaction. We expect to identify small molecules/fragments that have the potential to interrupt MEIG1/PACRG interaction and test the effect of selective small molecules/fragments using the established assay. Given that global Meig1 knockout mice and both single amino acid mutant MEIG1 and PACRG mice showed a male infertility only phenotype, targeting MEIG1/PACRG interaction is believed to cause few/no side effects. The ultimate goal of the proposed studies is to advance a male contraceptive to inhibit sperm formation/function to the stage of filing an investigational new drug (IND) application. The discovery and development of a male “pill” will benefit the general population and reduce unintended pregnancies.

总结 男性避孕药的发展远远落后于女性避孕药。当前物理 男性节育的选择在可靠性、使用的一致性和侵入性方面具有局限性， 分别通过降低睾丸激素水平来抑制精子生成也会导致不可接受的 副作用.因此，我们的长期目标是开发一种阻止晚期妊娠的避孕药 不使用激素的精子发生，因此效果可逆，副作用较少/无副作用 方面的影响.肩托是一个短暂的含有微管的结构，只存在于伸长的 精子细胞，以及manchette结构/功能的遗传破坏导致男性不育。重要的是， 我们发现，弯刀在精子发生中的功能需要以下因素的相互作用： 减数分裂表达基因1（MEIG 1）和Parkin共调节基因（PACRG）。MEIG 1基因的一个单点突变 破坏这两种蛋白质相互作用的PACRG也会破坏精子发生，导致纯雄性不育。 不孕MEIG 1和PACRG之间的相互作用在人类中是保守的。我们假设化合物 破坏MEIG 1/PACRG相互作用的药物可以开发成更安全有效的男性避孕药。 MEIG 1/PACRG结构的可用性使计算机虚拟和人工智能（AI）成为可能 筛选阻断MEIG 1/PACRG相互作用的小分子，并进行生物化学验证。因此 本申请的目的是进行计算机虚拟和AI筛选以鉴定 阻断MEIG 1和PACRG的相互作用，这可能成为男性避孕药的先导。本 最后，我们提供了一个强大的G.用于相互作用的princeps荧光素酶互补测定 MEIG 1和PACRG的表达，可以很容易地用于验证从MEIG 1和PACRG中鉴定的小分子的作用。 虚拟和AI屏幕。此外，化合物的片段文库可用于物理筛选， 中断MEIG 1/PACRG相互作用的片段也可用于未来的药物开发。因此，在本发明中， 我们提出了以下两个目标：1：完成计算机虚拟屏幕，并检查小的效果， 通过计算机模拟虚拟和AI筛选鉴定的分子对中断MEIG 1/PACRG相互作用的影响; 2： 筛选片段文库中破坏MEIG 1/PACRG相互作用的化合物。我们希望能找出 具有中断MEIG 1/PACRG相互作用的潜力的小分子/片段，并测试MEIG 1/PACRG相互作用的影响。 选择性小分子/片段。考虑到全球Meig 1基因敲除小鼠和 单氨基酸突变MEIG 1和PACRG小鼠均显示出雄性不育的表型，靶向 MEIG 1/PACRG相互作用被认为引起很少/没有副作用。拟议研究的最终目标 是将抑制精子形成/功能的男性避孕药推进到提交研究报告的阶段， 新药（IND）申请。男性“药丸”的发现和开发将使普通人群受益 减少意外怀孕。