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

开发用于避孕的精子特异性钾通道 SLO3 调节剂

• 批准号: 10671550
• 负责人: Jerod S. Denton
• 金额: $ 65.82万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-13 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10671550
• 关键词: Abortifacient Agents; Acrosome; Acrosome Reaction; Affect; Agglutinins; Biological Assay; Biology; Brain; Cells; Chemicals; Collection; Computer Assisted; Contraceptive Agents; Contraceptive Availability; Contraceptive Usage; Contraceptive methods; Data; Development; Drug Kinetics; Drug Targeting; Dyes; Electrophysiology (science); Excretory function; Feedback; Female; Female Contraceptive Agents; Female genitalia; Fertilization; Future; Grant; Heart; Hormones; Human; In Vitro; Infertility; Ion Channel; Knowledge; Lead; Libraries; Mammals; Membrane Potentials; Metabolism; Mus; Oocytes; Organ; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase; Physiology; Pisum sativum; Play; Potassium; Potassium Channel; Pregnancy; Process; Property; Reproductive Health; Research; Role; Seminal fluid; Specificity; Sperm Capacitation; Stains; Structure-Activity Relationship; Testing; Thallium; Woman; Work; absorption; cell motility; contraceptive target; drug development; drug metabolism; drug repurposing; high throughput screening; improved; in silico; in vivo; inhibitor; innovation; meter; patch clamp; potency testing; prevent; reproductive tract; scaffold; side effect; small molecule; small molecule inhibitor; sperm cell; sperm function; unintended pregnancy; voltage

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.

项目概要 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 副作用，4) 不依赖于激素。我们认为钾 (K+) 通道 SLO3 是一个 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；缺乏SLO3的小鼠 健康但不育，因为他们的精子未能经历与精子融合的能力所必需的过程 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（释放 顶体内容）。其次，这些过程发生在女性生殖道，因此针对 SLO3 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不会影响任何 女性体内的其他细胞。我们的目标是开发 SLO3 抑制剂，作为非激素药物 和可逆女性避孕药。为了实现我们的目标，在拨款的 R61 阶段，我们将： 1) 雇用 高通量筛选（HTS）以鉴定有效且特异性的 SLO3 通道小分子抑制剂，以及 2) 进行膜片钳电生理学以测试目标 1 中确定的 SLO3 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 SLO3 调节剂，4）确定 SLO3 抑制剂对人类精子 K+ 电流和人类精子功能的影响。 这里提出的研究将确定可发展成创新型女性的先导分子 通过靶向精子获能起作用的非激素避孕药。从这些获得的信息 研究还将为该领域贡献新知识，特别是更深入地了解离子的作用 精子生理学的通道。