World Health Organization (WHO) statistics show that of the over 200 million pregnancies worldwide peryear, 87 million pregnancies (42%) were unintended. In spite of the availability of female contraceptivemethods and condoms, in half of the unintended pregnancies the women reported to be using acontraceptive, and 46 million pregnancies were terminated by abortion. Thus, the NIH, IOM, and WHO haveidentified the need to develop novel reversible oral non-hormonal male contraceptive agents. The long termgoals of our research are 1) to identify viable targets in testis or in sperm important for male fertility that canbe exploited for development as reversible male contraceptive agents, and 2) to discover, design, test, anddemonstrate proof-of concept for novel non-hormonal small molecule agents that inhibit these testis orsperm targets. We have developed H2-Gamendazole, as a new class of indazole carboxylic acids thatspecifically cause premature release of spermatids from the testis. H2-Gamendazole is a highly promisingpotent and reversible non-hormonal male contraceptive agent that NICHD is currently evaluating inpreparation towards human clinical trials. Gamendazoles bind to two novel testis protein targets, Hsp90p andeEF1A that will be exploited for design and synthesis of new male contraceptive agents. To this end, thecentral hypothesis is that the reduction in function of HspSOp and eEF1A in testis by novel small moleculeinhibitors results in reversible late-stage anti-spermatogenic contraception. To achieve the goal of designingnew 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 anddetermine their anti-spermatogenic efficacy2. Define the binding site for Gamendazole analogues within Hsp90 and eEF1 A and delineate the 3-Dprotein-Gamendazole interactions within the docking sites3. Define the mechanism of action of Hsp90 and eEF1 A inhibitors that are reversibly antispermatogenicThe specific aims will be accomplished by cutting edge drug discovery and molecular approaches includinghigh throughput screening of over 120,000 compounds, x-ray crystallography of Hsp90 and eEF1A drugproteinco-crystals, 3-D modeling and structure activity relationships (SAR) to refine lead contraceptiveagents, and definition of the mechanism of action of the drug using molecular, cell biological, and proteomicapproaches 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 provideNIH with new chemical structures that can be added as pharmacological alternatives to Gamendazole fordrug development and clinical trials as reversible non-hormonal oral male contraceptives.
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