Targeting the MEIG1/PACRG interaction for male contraception.

针对男性避孕的 MEIG1/PACRG 相互作用。

基本信息

  • 批准号:
    10705689
  • 负责人:
  • 金额:
    $ 19.25万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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.
摘要 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存在局限性, 分别进行了分析。通过降低睾酮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月经后期的避孕药。 不使用激素的精子发生,因此这种效果是可逆的,而且副作用更少/不存在 效果。套筒是一种瞬时的微管结构,只有在伸长时才存在。 精子细胞,以及套筒结构/功能的遗传破坏会导致男性不育。重要的是 我们发现,弯刀在精子发生中的作用需要相互作用 减数分裂表达基因1(MEIG1)和Parkin共同调节基因(PACRG)。MEIG1基因的单点突变 或者,破坏这两种蛋白质相互作用的PACRG也会扰乱精子发生,导致纯男性 不孕不育。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相互作用的药物可以开发成更安全有效的男性避孕药。 MEIG1/PACRG结构的可用性使其能够在计算机虚拟和人工智能(AI)中 筛选阻止MEIG1/PACRG相互作用的小分子,并进行生化验证。因此, 本申请的目的是在硅胶虚拟和人工智能屏幕中进行识别 阻断MEIG1和PACRG的相互作用,可发展成为男性避孕药的先导。对这件事 最后,我们为这种相互作用提供了可靠的绿僵菌荧光素酶互补分析的初步数据。 MEIG1和PACRG,可以很容易地用来验证从 虚拟屏幕和人工智能屏幕。此外,化合物的片段库可用于物理屏幕和 中断MEIG1/PACRG相互作用的片段也可以用于未来的药物开发。因此, 我们提出了以下两个目标:1.完成了嵌入式虚拟屏幕的制作,并考察了小屏幕的显示效果 在中断MEIG1/PACRG相互作用的计算机虚拟和人工智能屏幕上识别的分子;2:到 筛选片段文库,寻找破坏MEIG1/PACRG相互作用的化合物。我们希望能确定 有可能中断MEIG1/PACRG相互作用并测试其效果的小分子/片段 使用已建立的分析方法选择小分子/片段。鉴于全球Meig1基因敲除小鼠和 单一氨基酸突变体MEIG1和PACRG小鼠都显示出只有男性不育的表型,靶向 MEIG1/PACRG相互作用被认为几乎没有副作用。拟议研究的最终目标是 是将一种抑制精子形成/功能的男性避孕药推进到提交调查报告的阶段 新药(IND)申请。男性避孕药的发现和发展将造福于普通民众 并减少意外怀孕。

项目成果

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Zhibing Zhang其他文献

Zhibing Zhang的其他文献

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{{ truncateString('Zhibing Zhang', 18)}}的其他基金

Intraflagellar transport (IFT) and sperm formation
鞭毛内运输 (IFT) 和精子形成
  • 批准号:
    10596173
  • 财政年份:
    2022
  • 资助金额:
    $ 19.25万
  • 项目类别:
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
  • 财政年份:
    2022
  • 资助金额:
    $ 19.25万
  • 项目类别:
Intraflagellar transport (IFT) and sperm formation
鞭毛内运输 (IFT) 和精子形成
  • 批准号:
    10445709
  • 财政年份:
    2022
  • 资助金额:
    $ 19.25万
  • 项目类别:
The role of transcription factor S-SOX5 in male fertility and sperm flagella formation
转录因子S-SOX5在男性生育力和精子鞭毛形成中的作用
  • 批准号:
    9225891
  • 财政年份:
    2017
  • 资助金额:
    $ 19.25万
  • 项目类别:
Dissection of the structural basis of MEIG1 in assembling sperm flagella
剖析MEIG1组装精子鞭毛的结构基础
  • 批准号:
    8483624
  • 财政年份:
    2013
  • 资助金额:
    $ 19.25万
  • 项目类别:
Dissection of the structural basis of MEIG1 in assembling sperm flagella
剖析MEIG1组装精子鞭毛的结构基础
  • 批准号:
    9293129
  • 财政年份:
    2013
  • 资助金额:
    $ 19.25万
  • 项目类别:
Dissection of the structural basis of MEIG1 in assembling sperm flagella
剖析MEIG1组装精子鞭毛的结构基础
  • 批准号:
    8849469
  • 财政年份:
    2013
  • 资助金额:
    $ 19.25万
  • 项目类别:
Dissection of the structural basis of MEIG1 in assembling sperm flagella
剖析MEIG1组装精子鞭毛的结构基础
  • 批准号:
    8675898
  • 财政年份:
    2013
  • 资助金额:
    $ 19.25万
  • 项目类别:
Dissection of the structural basis of MEIG1 in assembling sperm flagella
剖析MEIG1组装精子鞭毛的结构基础
  • 批准号:
    9067160
  • 财政年份:
    2013
  • 资助金额:
    $ 19.25万
  • 项目类别:

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