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

基本信息

批准号：
10598585
负责人：
MARTIN M. MATZUK
金额：
$ 70.24万
依托单位：
UNIVERSITY OF MISSOURI-COLUMBIA
依托单位国家：
美国
项目类别：
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/10598585
关键词：
3-Dimensional Address Adolescent Antibodies Azoles Back Binding Cell Survival Cells Cervical Cessation of life Chemistry Contraceptive Agents Contraceptive Availability Contraceptive methods DNA Dose Ejaculation Elastases Embryo Epithelial Cells Failure Female Female Contraceptive Agents Fertility Fertilization Film Fluorides Gel Genes Goals Health Healthcare Human Hyperviscosity In Vitro Infertility Kinetics Lead Libraries Liquid substance Macaca mulatta Male Infertility Medical Methods Molecular Mucous body substance Mus Outcome Peptide Hydrolases Permeability Pharmacodynamics Pilot Projects Porifera Pregnancy Pregnancy Rate Pregnancy in Adolescence Process Prostate Prostate-Specific Antigen Proteins Public Health Reporting Research Research Personnel Resources Risk Seminal Plasma Seminal fluid Series Serine Protease Serine Proteinase Inhibitors Site Specificity Sperm Motility Sperm Transport Spermatocidal Agents System Technology Teenagers Testing Thrombin Tight Junctions Time Tissues Titrations Toxic effect United States Unwanted pregnancy Uterus Vagina Viscosity Withdrawal Woman Work analog candidate validation care burden cervicovaginal chymotrypsin condoms contraceptive efficacy enzyme activity experimental study hormonal contraception implantation improved in vitro Assay in vivo inhibitor innovation men nanomolar natural Blastocyst Implantation nonhuman primate novel novel strategies novel therapeutics pharmacologic pregnancy prevention prevent protein function prototype reproductive tract reversible contraceptive screening small molecule small molecule inhibitor small molecule libraries sperm cell sperm function statistics three dimensional cell culture translational approach unintended pregnancy

项目摘要

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.

项目概要/摘要虽然激素避孕方法非常有效，但它们并不是许多女性的选择。国家卫生统计报告表明，按需非处方 (OTC) 避孕药具（即杀精剂和避孕套）是许多女性，尤其是青少年的首选产品。 OTC 方法的失败率很高，因此，青少年怀孕占 70% 以上。因此，迫切需要新的和改进的方法。在本提案中，我们将探索一种新的女性避孕方法。两个过程：1）阻止射精后的精液；2）抑制女性生殖系统中的精子活力射精后，精液通过前列腺丝氨酸从凝胶状变为水状稠度。因此，该应用的中心假设是药理学。阻止精液液化通过阻止精子到达该部位来提供避孕效果我们之前的工作表明，丝氨酸蛋白酶抑制剂可以有效阻断这两者。根据这些发现，捕获了这种小物质并阻止了雌性小鼠的怀孕。具有靶向活性的 KLK3 分子抑制剂可被开发用作新型、非激素、完全女性可逆避孕药在该应用中，一组研究人员将测试小型避孕药的作用。 KLK3 分子抑制剂对人类精液和精子功能、雌性恒河猴妊娠预防的影响除了原型抑制剂之外，还将鉴定出 KLK3 的新型小分子抑制剂。假设将在三个具体目标中进行检验：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“命中”化合物的细胞毒性人类宫颈/阴道细胞和 3D 阴道培养物，3) 表征避孕功效和特定 KLK3 抑制剂在雌性恒河猴中的药效学/动力学，以及 4) 鉴定新药- 就像 DNA 编码化学库中的 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酶抑制剂是否可以开发为第一个避孕产品（即，薄膜/海绵）可防止精液液化并抑制精子功能。