In the previous U54 funding period, we focused on developing a class of novel snnall molecule oral nonhormonal anti-spermatogenic contraceptive agents. Of these, H2-gamendazole (H2-GMZ) is now identified as most promising, with 100% oral bioavailability, and 100% infertility followed by 100% recovery of fertility in rats, with no loss in mating behavior. Pilot proof-of-concept studies in non-human primates showed completely reversible declines in spermatid count and semen sperm count with no adverse side effects. H2-GMZ is rapidly absorbed by Sertoli cells and appears to cause premature release of spermatids via binding to and disruption of the eEF1A-F-actin-bundles associated with the apical ectoplasmic specializations. An alternative compound, narciclasine (NAR), has also been identified with similar disruptive effects on the non canonical eEF1A-actin bundling function in Sertoli cells. In order to achieve the overall goal of moving H2 GMZ towards FDA IND status and clinical trials, critical efficacy data in non-human primates, elaborate all of the steps in the mechanism of action of H2-GMZ, and prudent discovery of alternative chemical leads are needed. Thus, the overall hypothesis for this project is that H2-GMZ and other small molecules that reversibly disrupt eEFIA-actin bundling in Sertoli cells can be developed as clinically useful reversible anti-spermatogenic contraceptive agents.
Three specific aims are proposed to achieve these goals:
Aim 1 : Determine proof-of concept efficacy and pharmacokinetics of oral low-dose H2-GMZ as a reversible anti-spermatogenic contraceptive agent in non-human primates.
Aim 2 : Determine the mechanism of H2-GI /IZ and novel small molecule-elicited changes in eEF1A actinbundling and post-translational modification on premature loss of spermatids.
Aim 3 : Identify and optimize other novel selective small molecules that mimic H2-GMZ-eEF1A actions as anti- spermatogenic contraceptive agents. Success in these endeavors will provide essential data needed to enable ultimately moving H2-GMZ into pre-clinical toxicology and registration as an FDA IND for the start of clinical trials in humans.
Thls project is highly relevant to the goals of the Contraceptive Development Research Centers Program as it will provide data essential to achieve the ultimate goal of making H2- gamendazole a clinically useful contraceptive product. As such, H2-gamendazole is a non-hormonal male contraceptive agent that shows 100% infertility with full recovery, and is nearly ready to approach the FDA for registration as an IND. The project will help complete the studies necessary to achieve this goal, and to identify similar contraceptive agents as alternative leads with similar contraceptive mechanisms of action.