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

项目摘要 在美国，意外怀孕的高发生率（约45%）主要是由于不正确或不一致的使用 避孕药具，这表明现有的避孕药具不能满足妇女的需要。一个理想的女性 避孕药将：1）在预防怀孕方面非常有效，2）不作为堕胎药，3）没有 负面副作用，4）不依赖激素。我们认为钾离子通道SLO 3是一个钾离子通道。 这是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 SLO 3频道的独特之处。首先，SLO 3是精子获能所必需的;缺乏SLO 3的小鼠 是健康的，但不育，因为他们的精子未能经历必要的过程，他们的能力融合， 卵母细胞的超活化（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）。第二，这些过程发生在女性生殖道，因此靶向SLO 3的药物 将是一种有效的、非激素的、非堕胎的女性避孕药。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，因此针对这一通道的避孕药将影响没有 另一个细胞我们的目标是开发SLO 3的抑制剂， 和可逆的女性避孕药。为了达到我们的目标，在R61阶段的补助金，我们将：1）雇用 高通量筛选（HTS），以鉴定SLO 3通道的有效和特异性小分子抑制剂，以及 2)进行膜片钳电生理学以测试目的1中鉴定的SLO 3抑制剂的效力和选择性。在 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K+电流和人精子功能的影响 这里提出的研究将确定铅分子，可以发展成为一个创新的一类女性 非激素类避孕药，通过靶向精子获能而起作用。从这些信息中获得的信息 这些研究还将为该领域提供新的知识，特别是更深入地了解离子的作用。 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.