Disruption of semen liquefaction using specific KLK3 inhibitors as a new contraceptive

使用特定 KLK3 抑制剂作为新避孕药破坏精液液化

• 批准号: 10682061
• 负责人: MARTIN M. MATZUK
• 金额: $ 64.52万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-11 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10682061
• 关键词: Disruption; semen; liquefaction; using; specific; Disruption; semen; liquefaction; using; specific

PROJECT SUMMARY/ABSTRACT While hormonal contraceptive methods are highly effective, they are not the method of choice for many women. The National Health Statistic Report indicates that on-demand over-the-counter (OTC) contraceptives (i.e., spermicides and condoms) are the products of choice for many women, especially teenagers. Unfortunately, OTC methods have high failure rates. As a result, teenage pregnancies contribute to more than 70% of unintended pregnancy rates in the United States. Therefore, there is a critical need for new and improved on- demand methods for women. In this proposal, we will explore a new female contraceptive method that will target two processes: 1) blocking post-ejaculated semen and 2) inhibiting sperm motility in the female reproductive tract. After ejaculation, semen changes from a gel-like to a watery consistency via the prostate-derived serine protease called kallikrein 3 (KLK3). Therefore, the central hypothesis for this application is that pharmacologic blockade of semen liquefaction provides a contraceptive effect by blocking sperm from reaching the site of fertilization. Our previous work showed that a serine protease inhibitor effectively blocked those two processes and prevented pregnancy in female mice. Based on these findings, it is hypothesized that small molecule KLK3 inhibitors with targeted activity can be developed for use as novel, non-hormonal, fully reversible contraceptives for women. In this application, a team of investigators will test the action of small molecule KLK3 inhibitor(s) in human semen and sperm function, pregnancy prevention in female rhesus macaques, and will identify novel small molecules inhibitors of KLK3 in addition to the prototype inhibitor. The hypothesis will be tested in three Specific Aims: 1) to characterize the contraceptive potential of specific KLK3 inhibitors in human semen, 2) To evaluate the cellular toxicity of specific KLK3 inhibitor and “hit” compound(s) in human cervical/vaginal cells and 3D vaginal cultures, 3) to characterize the contraceptive efficacy and pharmacodynamics/kinetics of specific KLK3 inhibitor in female rhesus macaques, and 4) To identify novel drug- like KLK3-specific inhibitors from DNA-encoded chemical libraries. Upon completion of this study, we will be able to demonstrate whether serine protease inhibitor can be developed as the first contraceptive product (i.e., film/sponge) that prevents semen liquefaction as well as inhibits the sperm function.

项目摘要/摘要 尽管激素避孕方法非常有效，但它们并不是许多女性的选择方法。 国家健康统计报告表明，按需非处方（OTC）避孕药（即 精子剂和避孕套是许多女性，尤其是青少年的首选产品。很遗憾， OTC方法的故障率很高。结果，青少年怀孕贡献了超过70％ 美国意外怀孕率。因此，迫切需要新的和改进 女性的需求方法。在此提案中，我们将探索一种新的女性避孕方法，该方法将针对 两个过程：1）阻止骨后精液和2）抑制女性生殖的精子运动 道。射精后，精液通过前列腺衍生的系列从类似凝胶的变为水的一致性变化 蛋白酶称为Kallikrein 3（KLK3）。因此，此应用的中心假设是药理学 精液液化的封锁通过阻止精子到达现场来提供避孕效果 受精。我们以前的工作表明，丝氨酸蛋白抑制剂有效地阻断了这两个 雌性小鼠的过程并预防妊娠。基于这些发现，假设很小 具有靶向活性的分子KLK3抑制剂可以用作新型，非激素，完全完全 女性的可逆避孕药。在此应用程序中，一组调查人员将测试小规模的行动 人类精液和精子功能中的分子KLK3抑制剂，雌性恒河猴的妊娠预防 猕猴，除原型抑制剂外，还将鉴定出KLK3的新型小分子抑制剂。 假设将以三个特定目的进行检验：1）表征特定klk3的避孕潜力 人类精液中的抑制剂，2）评估特定KLK3抑制剂和“ hit”化合物的细胞毒性 人宫颈/阴道细胞和3D阴道培养物，3）表征避孕效率和 雌性猕猴中特异性KLK3抑制剂的药效学/动力学，4） 就像来自DNA编码化学文库的KLK3特异性抑制剂一样。完成这项研究后，我们将能够 证明丝氨酸蛋白抑制剂是否可以作为第一种避孕产物开发（即 膜/海绵）可防止精液液化并抑制精子功能。