Developing modulators of the sperm-specific potassium channel SLO3 for contraception

项目总结 在美国，意外怀孕的高比率(~45%)很大程度上是由于不正确或不一致地使用 避孕药具，表明现有的避孕药具不能满足妇女的需要。理想的女性 避孕药将：1)高效地预防怀孕，2)不起到堕胎的作用，3)没有 不良反应，以及4)不依赖激素。我们认为钾(K+)通道SLO_3是一个 开发符合这些标准的避孕药的理想目标。这个想法是建立在几个基础上的 SLO_3通道的独特方面。首先，精子获能绝对需要SLO_3；缺乏SLO_3的小鼠 是健康但不育的，因为他们的精子不能经历与 卵母细胞的过度激活(受精所必需的一种强有力的运动)和顶体反应(释放) 顶体内容)。其次，这些过程发生在女性生殖道，所以靶向SLO_3的药物 将是一种有效的、不含激素、不会流产的女性避孕药。最后，SLO_3通道仅 在人类和其他哺乳动物的精子细胞中表达，所以针对这一通道的避孕药将影响NO 女人身体里的另一个细胞。我们的目标是开发一种非荷尔蒙的SLO_3抑制剂。 和可逆的女性避孕药。为了实现我们的目标，在赠款的R61阶段，我们将：1)雇用 高通量筛选(HTS)以确定有效和特定的SLO_3通道小分子抑制物，以及 2)进行膜片钳电生理学以测试AIM 1中确定的SLO_3抑制剂的效力和选择性。 在R33阶段，我们将：3)通过药物化学优化SLO_3调节剂，4)确定 SLO_3抑制剂对人精子钾电流和精子功能的影响 这里提出的研究将确定可以发展成创新的女性阶层的铅分子。 以精子获能为靶点的非激素避孕药。从这些网站获得的信息 研究还将为该领域提供新的知识，特别是对离子的作用有更深入的了解 精子生理学中的通道。

PROJECT SUMMARY The high (~45%) rate of unintended pregnancies in the US is largely due to incorrect or inconsistent use of contraceptives, indicating that available contraceptives are failing to meet women's needs. An ideal female contraceptive will: 1) be highly effective at preventing pregnancy, 2) not act as an abortifacient, 3) have no negative side effects, and 4) not depend on hormones. We propose that the potassium (K+) channel SLO3 is an ideal target for the development of a contraceptive that meets these criteria. This idea is founded on several unique aspects of SLO3 channels. First, SLO3 is absolutely required for sperm capacitation; mice lacking SLO3 are healthy but infertile because their sperm fail to undergo processes essential to their ability to fuse with an oocyte, hyperactivation (a vigorous type of motility essential to fertilization) and the acrosome reaction (release of the acrosome content). Second, these processes occur in the female genital tract, so a drug targeting SLO3 will be an effective, non-hormonal, non-abortifacient, female contraceptive. Finally, SLO3 channels are only expressed in sperm cells in humans and other mammals, so a contraceptive targeting this channel will affect no other cell in a woman's body. Our objective here is to develop inhibitors of SLO3 that will act as non-hormonal and reversible female contraceptives. To achieve our objective, in the R61 Phase of the grant we will: 1) employ high-throughput screening (HTS) to identify potent and specific small-molecule inhibitors of SLO3 channels, and 2) perform patch clamp electrophysiology to test potency and selectivity of SLO3 inhibitors identified in aim 1. In the R33 Phase we will: 3) optimize SLO3 modulators via medicinal chemistry and 4) determine the effects of SLO3 inhibitors on human sperm K+ currents and human sperm function. The research proposed here will identify lead molecules that can be developed into an innovative class of female non-hormonal contraceptives that act by targeting sperm capacitation. The information obtained from these studies will also contribute new knowledge to the field, specifically a deeper understanding of the role of ion channels in sperm physiology.