Targeting the MEIG1/PACRG interaction for male contraception.

针对男性避孕的 MEIG1/PACRG 相互作用。

• 批准号: 10705689
• 负责人: Zhibing Zhang
• 金额: $ 19.25万
• 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/10705689
• 关键词: Affinity; Amino Acids; Animals; Artificial Intelligence; Binding; Biochemical; Biological Assay; Cell Communication; Cells; Collaborations; Complement; Complex; Contraceptive Agents; Couples; 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; Meiosis Inhibition; 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; 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.

概括 男性避孕药的发展远远落后于女性避孕药。电流物理 男性节育的选择在可靠性，使用的一致性和侵入性方面有局限性， 通过降低睾丸激素水平抑制精子的产生也将导致不可接受 副作用。这就是我们的长期目标是开发一种避孕药，以阻止 精子发生不使用马，使得效果可逆，较少/无边是可逆的 效果。该猎物是一种瞬态含微管的结构，仅在拉长中存在 精子和遗传破坏的生产力结构/功能导致男性不育症。重要的是， 我们发现，砍刀在精子发生中的功能需要 减数分裂表达基因1（Meig1）和帕金共同调节的基因（PACRG）。 Meig1中的一个点突变 或破坏两种蛋白质相互作用的PACRG也破坏了精子发生，导致纯男性 不育。 Meig1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MEIG1/PACRG的相互作用可以发展为安全有效的男性避孕药。 MEIG1/PACRG结构的可用性使得在硅虚拟和人工智能（AI）中成为可能 筛选的小分子，可阻止MEIG1/PACRG相互作用，并具有生化验证效果。那， 本应用的目的是在硅虚拟和AI屏幕中进行操作，以识别小分子 阻止Meig1和Pacrg的相互作用，这些相互作用可以发展为男性避孕药的铅。对此 最后，我们为互动的强大的G. princeps荧光素酶完成分析提供了初步数据 Meig1和pacrg的作品，可以很容易地用于验证从 虚拟和AI屏幕。此外，适用于化合物的片段可用于物理屏幕和 中断MEIG1/PACRG相互作用的碎片也可以用于药物开发。那， 我们提出以下两个目的：1：完成硅虚拟屏幕中的内容并检查小的效果 在中断MEIG1/PACRG相互作用时，由硅虚拟中的分子和AI屏幕鉴定出来； 2：到 筛选片段库中的化合物破坏MEIG1/PACRG相互作用。我们希望确定 小分子/片段有可能中断Meig1/pacrg相互作用并测试的影响 选择性小分子/片段使用已建立的测定法。鉴于全球Meig1淘汰小鼠和 单氨基酸突变体Meig1和Pacrg小鼠均显示出仅雄性不育症的表型 Meig1/Pacrg相互作用被认为会引起几乎没有/无副作用。拟议研究的最终目标 是为了推进男性避孕药，以抑制精子形成/功能 新药（IND）应用。男性“药丸”的发现和发展将使普通人群受益 并减少意外怀孕。