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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.

项目总结/文摘