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.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Specialized Center--Cooperative Agreements (U54)
Project #
Application #
Study Section
Special Emphasis Panel (ZHD1)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Kansas
Kansas City
United States
Zip Code
Olesen, Sanne H; Ingles, Donna J; Zhu, Jin-Yi et al. (2015) Stability of the human Hsp90-p50Cdc37 chaperone complex against nucleotides and Hsp90 inhibitors, and the influence of phosphorylation by casein kinase 2. Molecules 20:1643-60
Agbor, Valentine A; Tao, Shixin; Lei, Ning et al. (2013) A Wt1-Dmrt1 transgene restores DMRT1 to sertoli cells of Dmrt1(-/-) testes: a novel model of DMRT1-deficient germ cells. Biol Reprod 88:51
McDermott, Jeffrey P; Sanchez, Gladis; Chennathukuzhi, Vargheese et al. (2012) Green fluorescence protein driven by the Na,K-ATPase *4 isoform promoter is expressed only in male germ cells of mouse testis. J Assist Reprod Genet 29:1313-25
Martin, Mathew P; Alam, Riazul; Betzi, Stephane et al. (2012) A novel approach to the discovery of small-molecule ligands of CDK2. Chembiochem 13:2128-36
Jimenez, Tamara; Sanchez, Gladis; Blanco, Gustavo (2012) Activity of the Na,K-ATPase ýý4 isoform is regulated during sperm capacitation to support sperm motility. J Androl 33:1047-57
Matts, Robert L; Brandt, Gary E L; Lu, Yuanming et al. (2011) A systematic protocol for the characterization of Hsp90 modulators. Bioorg Med Chem 19:684-92
Jimenez, Tamara; Sanchez, Gladis; McDermott, Jeffrey P et al. (2011) Increased expression of the Na,K-ATPase alpha4 isoform enhances sperm motility in transgenic mice. Biol Reprod 84:153-61
Betzi, Stephane; Alam, Riazul; Martin, Mathew et al. (2011) Discovery of a potential allosteric ligand binding site in CDK2. ACS Chem Biol 6:492-501
Jimenez, Tamara; McDermott, Jeffrey P; Sanchez, Gladis et al. (2011) Na,K-ATPase alpha4 isoform is essential for sperm fertility. Proc Natl Acad Sci U S A 108:644-9
Li, Zhenghe; Pogany, Judit; Tupman, Steven et al. (2010) Translation elongation factor 1A facilitates the assembly of the tombusvirus replicase and stimulates minus-strand synthesis. PLoS Pathog 6:e1001175

Showing the most recent 10 out of 16 publications