SLO3 K Channel: A Novel Target for Contraception

SLO3 K 通道：避孕的新目标

• 批准号: 9548332
• 负责人: Celia M Santi
• 金额: $ 27.82万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-13 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9548332
• 关键词: Abortifacient Agents; Acrosome; Acrosome Reaction; Adverse effects; Affect; Affinity; Biological Assay; Biology; Cells; Chemicals; Contraceptive Agents; Contraceptive Availability; Contraceptive Usage; Contraceptive methods; Development; Drug Targeting; Electrophysiology (science); Ensure; Exhibits; Family; Female; Female Contraceptive Agents; Fertilization; Fluorescence; Gold; Hormones; Human; Infertility; Institutes; Ion Channel; Knowledge; Lead; Libraries; Male Contraceptive Agents; Mammals; Mus; Oocytes; Pharmaceutical Chemistry; Physiology; Potassium; Potassium Channel; Powder dose form; Pregnancy; Process; Research; Role; Side; Sperm Capacitation; Spermatogenesis; Techniques; Testing; Thallium; Universities; Washington; Woman; base; cell motility; contraceptive target; experimental study; high throughput screening; inhibitor/antagonist; innovation; inward rectifier potassium channel; member; nanomolar; novel; patch clamp; premature; prevent; reproductive tract; response; screening; small molecule inhibitor; sperm cell; sperm function; stable cell line; unintended pregnancy; vector

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.

美国意外怀孕率较高（约 45%），很大程度上是由于不正确或不一致的使用 避孕药具，表明现有的避孕药具无法满足妇女的需求。一个理想的女性 避孕药将： 1) 非常有效地预防怀孕，2) 不作为堕胎药，3) 没有作用 副作用，4) 不依赖于激素。我们建议钾 (K+) 通道 SLO3 是 开发符合这些标准的避孕药具的理想目标。这个想法建立在几个基础上 SLO3 通道的独特之处。首先，SLO3对于精子获能是绝对必需的；小鼠缺乏 SLO3 是健康的，但不育，因为它们的精子无法经历融合能力所必需的过程 卵母细胞过度激活（受精所必需的一种剧烈运动）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中，因此药物 以 SLO3 为目标的药物将是一种有效、非激素、非堕胎剂的女性避孕药。最后，SLO3 通道仅在人类和其他哺乳动物的精子细胞中表达，因此针对该通道的避孕药 通道不会影响女性体内的其他细胞。我们的目标是开发 SLO3 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) 以鉴定有效且特异性的 SLO3 小分子抑制剂，2) 优化 SLO3 通过药物化学调节剂，3) 确定 SLO3 抑制剂对精子功能的影响。 这里提出的研究将确定可以开发成一类创新药物的先导分子。 通过靶向精子获能起作用的女性避孕药。作为附带好处，该项目还可能产生 SLO3 激活剂，可以测试其促进精子过早获能的能力。这样的 然后可以将化合物开发为非激素和可逆的男性避孕药（SLO3 不是 精子发生所需的）。从这些研究中获得的信息也将贡献新的知识 到该领域，特别是更深入地了解离子通道在精子生理学中的作用。