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.

项目摘要 在美国，意外怀孕的高（约45％）主要是由于不正确或不一致的使用 避孕药具，表明可用的避孕药未能满足妇女的需求。理想的女性 避孕药将：1）在预防怀孕方面非常有效，2）不充当或 负副作用，4）不依赖激素。我们建议钾（K+）通道Slo3是 制定符合这些标准的避孕药的理想目标。这个想法建立在几个 Slo3通道的独特方面。首先，精子电容绝对需要SLO3；缺乏Slo3的小鼠 健康但不育是因为他们的精子无法接受与它们融合的能力至关重要的过程 卵母细胞，过度激活（一种对受精至关重要的剧烈运动）和Adrosom反应（释放 ACROSOMES含量）。其次，这些过程发生在女性生殖道中，因此靶向Slo3的药物 将是一种有效的，非荷尔蒙，非劳化，女性避孕药。最后，Slo3频道仅是 在人类和其他哺乳动物中的精子细胞中表达，靶向此通道的避孕药会影响否 女人体内的其他细胞。我们的目的是开发SLO3的抑制剂，该抑制剂将充当非激素 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），以识别SLO3通道的有效和特定的小分子抑制剂，以及 2）执行贴片夹电生理学以测试AIM 1中鉴定的Slo3抑制剂的效力和选择性。 R33阶段我们将：3）通过药物化学优化SLO3调节剂，4）确定 对人类精子K+电流和人类精子功能的SLO3抑制剂。 这里提出的研究将确定可以发展为创新的女性类别的铅分子 通过靶向精子电容来起作用的非激素避孕药。从这些获得的信息 研究还将为该领域提供新知识，特别是对离子的作用有更深入的了解 精子生理学的渠道。