Development of regulatory domain inhibitors of ADCY10

项目3 新鲜射出的哺乳动物精子不能使卵子受精。他们获得了受精 射精后数小时内通过女性生殖道的能力 这一过程被称为获能。可溶性腺酰环化酶(SAC：ADCY10)是一种非激素性物质 靶标对精子获能和男性生育能力至关重要。药物性SAC抑制剂阻断 精子的体外功能和两个不同的SAC基因敲除(KO)小鼠品系表现出男性特异性 不育而不表现出其他明显的表型。在此测试的总体假设 避孕研究中心(CRC)是可以设计SAC抑制剂的 适当的剂量，以阻止精子功能，同时最大限度地减少不良副作用。我们有 最近发现了SAC的小分子激活剂，它们通过外部调节结构域发挥作用 SAC的催化核心。这些激活剂选择性地刺激精子中丰富的SAC亚型。在……里面 这个避孕开发研究项目，我们假设一类新的抑制剂， 与这些调控结构域结合，将通过选择性地抑制SAC来阻止获能 精子的功能。以SAC抑制剂为靶点的监管领域将产生更少的不良反应 副作用。在这个项目中，我们提出了一种高通量策略来识别小分子 这会阻止精子囊的激活并阻止获能。合适的监管领域 SAC抑制剂将接受一系列精炼周期和体内研究的描述 在本《儿童权利公约》的项目1和2中。该项目的最终目标是开发选择性的抑制剂 用于精子中的SAC亚型，作为口服非激素避孕药的先导化合物。

Project 3 Freshly ejaculated mammalian sperm are unable to fertilize an egg. They acquire fertilizing capacity in the hours following ejaculation, as they pass through the female reproductive tract, in a process known as capacitation. Soluble adenylyl cyclase (sAC: ADCY10) is a non-hormonal target essential for sperm capacitation and male fertility. Pharmacological sAC inhibitors block sperm functions in vitro and two distinct sAC knockout (KO) mouse strains exhibit male-specific sterility without exhibiting other overt phenotypes. The overall hypothesis tested in this Contraception Research Center (CRC) is that sAC inhibitors can be designed which can be appropriately dosed to block sperm functions while minimizing undesirable side effects. We have recently identified small molecule activators of sAC which function via regulatory domains outside sAC’s catalytic core. These activators selectively stimulate isoforms of sAC enriched in sperm. In this Contraception Development Research Project, we hypothesize that a new class of inhibitors, which binds to these regulatory domains, will prevent capacitation by selectively inhibiting sAC functions in sperm. Regulatory-domain targeting sAC inhibitors would produce fewer undesirable side effects. In this Project, we propose a high throughput strategy to identify small molecules which block the activation of sperm sAC and prevent capacitation. Suitable regulatory domain sAC inhibitors will be subjected to the pipeline of refinement cycles and in vivo studies described in Projects 1 and 2 of this CRC. The ultimate goal of this Project is to develop inhibitors selective for sAC isoforms in sperm as lead compounds for oral, non-hormonal contraceptives.