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.
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