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Novel Male Contraceptive Agents that Target HSP90 and Elongation Factor 1A

针对 HSP90 和伸长因子 1A 的新型男性避孕药

基本信息

批准号：
8066371
负责人：
JOSEPH S TASH
金额：
$ 44.28万
依托单位：
UNIVERSITY OF KANSAS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-03-01 至 2012-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8066371
关键词：
3-Dimensional Actins Adverse effects Affect Affinity Antispermatogenic Agents Binding Binding Proteins Binding Sites Biological Bundling Cancer cell line Carboxylic Acids Cell Line Cells Chemical Agents Chemical Structure Client Clinical Trials Complex Contraceptive Agents Contraceptive methods Crystallography Data Development Docking Drug Design Drug effect disorder Drug usage Elongation Factor Environment Event Family Female Contraceptive Agents Fertility Gene Expression Regulation Gene Proteins Genes Goals Guanine Nucleotide Exchange Factors Guanosine Triphosphate Hand Heat-Shock Proteins 90 Hormonal Human Hydrolysis In Vitro Indazoles Individual Inhibitory Concentration 50 Laboratories Lead Legal patent Ligands Lonidamine Male Contraceptive Agents Maps Modeling Molecular National Institute of Child Health and Human Development New Agents Nucleotides Oral Outcome Pathway interactions Pharmaceutical Chemistry Pharmaceutical Preparations Phase Phase I Clinical Trials Population Pregnancy Preparation Process Production Proteins Proteomics Rattus Recording of previous events Reporting Reproductive Biology Research Reverse Transcriptase Polymerase Chain Reaction Ribonucleases Signal Pathway Site Spermatids Spermatocytes Spermatogenesis Spermatogenic Cell Staging Structure Structure-Activity Relationship Testing Testis Translations United States National Institutes of Health Woman Work Workplace World Health Organization abortion analog base condoms crosslink design drug development drug discovery experience high throughput screening in vivo inhibin B inhibitor/antagonist innovation male model design novel pre-clinical premature protein protein interaction protein structure response sertoli cell small molecule sperm cell statistics success three dimensional structure unintended pregnancy

项目摘要

World Health Organization (WHO) statistics show that of the over 200 million pregnancies worldwide per year, 87 million pregnancies (42%) were unintended. In spite of the availability of female contraceptive methods and condoms, in half of the unintended pregnancies the women reported to be using a contraceptive, and 46 million pregnancies were terminated by abortion. Thus, the NIH, IOM, and WHO have identified the need to develop novel reversible oral non-hormonal male contraceptive agents. The long term goals of our research are 1) to identify viable targets in testis or in sperm important for male fertility that can be exploited for development as reversible male contraceptive agents, and 2) to discover, design, test, and demonstrate proof-of concept for novel non-hormonal small molecule agents that inhibit these testis or sperm targets. We have developed H2-Gamendazole, as a new class of indazole carboxylic acids that specifically cause premature release of spermatids from the testis. H2-Gamendazole is a highly promising potent and reversible non-hormonal male contraceptive agent that NICHD is currently evaluating in preparation towards human clinical trials. Gamendazoles bind to two novel testis protein targets, Hsp90p and eEF1A that will be exploited for design and synthesis of new male contraceptive agents. To this end, the central hypothesis is that the reduction in function of HspSOp and eEF1A in testis by novel small molecule inhibitors results in reversible late-stage anti-spermatogenic contraception. To achieve the goal of designing new male contraceptive agents, the following Specific Aims will be accomplished: 1. Identify chemically distinct small molecules that bind to Hsp90¿ or eEF1 A like Gamendazole and determine their anti-spermatogenic efficacy 2. Define the binding site for Gamendazole analogues within Hsp90¿ and eEF1 A and delineate the 3-D protein-Gamendazole interactions within the docking sites 3. Define the mechanism of action of Hsp90¿ and eEF1 A inhibitors that are reversibly antispermatogenic The specific aims will be accomplished by cutting edge drug discovery and molecular approaches including high throughput screening of over 120,000 compounds, x-ray crystallography of Hsp90 and eEF1A drugprotein co-crystals, 3-D modeling and structure activity relationships (SAR) to refine lead contraceptive agents, and definition of the mechanism of action of the drug using molecular, cell biological, and proteomic approaches to define targets of reversible versus irreversible anti-spermatogenic male contraceptive agents. Proof-of-concept demonstration that the new agents are reversible inhibitors of spermatogenesis will provide NIH with new chemical structures that can be added as pharmacological alternatives to Gamendazole for drug development and clinical trials as reversible non-hormonal oral male contraceptives.

世界卫生组织（世卫组织）的统计数据显示，在全世界2亿多例怀孕中