SLO3 K Channel: A Novel Target for Contraception

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 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， SLO 3是健康的，但不育，因为他们的精子未能经历必要的过程，他们的融合能力 与卵母细胞，超活化（一种对受精至关重要的活力类型）和顶体反应 （顶体内容物的释放）。其次，这些过程发生在女性生殖道，所以药物 靶向SLO 3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，因此针对此的避孕药 通道不会影响女性体内的其他细胞。我们的目标是开发SLO 3的抑制剂， 作为非激素和可逆的女性避孕药。为了实现我们的目标，我们将1）采用高通量 筛选（HTS）以鉴定SLO 3的有效和特异性小分子抑制剂，2）优化SLO 3 通过药物化学研究SLO 3调节剂，3）确定SLO 3抑制剂对精子功能的影响。 这里提出的研究将确定铅分子，可以发展成为一个创新的类， 通过精子获能起作用的女性避孕药。作为一个附带的好处，这个项目也可能产生 SLO 3的活化剂，可以测试其促进过早精子获能的能力。等 然后，化合物可以被开发为非激素和可逆的男性避孕药（SLO 3不是 精子发生所需）。从这些研究中获得的信息也将贡献新的知识 该领域，特别是更深入地了解离子通道在精子生理学中的作用。

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 we will 1) employ high-throughput screening (HTS) to identify potent and specific small-molecule inhibitors of SLO3, 2) optimize SLO3 modulators via medicinal chemistry and 3) determine the effects of SLO3 inhibitors on sperm function. The research proposed here will identify lead molecules that can be developed into an innovative class of female contraceptives that act by targeting sperm capacitation. As a side benefit, this project may also produce activators of SLO3 that can be tested for their ability to promote premature sperm capacitation. Such compounds could then be developed as non-hormonal and reversible male contraceptives (SLO3 is not required for spermatogenesis). 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.