Increased population growth has a wide range of impacts on human health and can only be controlled by the development of new contraceptive methods. One strategy has been to capitalize on our emerging understanding of the molecular mediators of fertilization to design novel mechanism-based antifertility agents. Specifically, fertilization is the result of a precisely coordinated series of cellular interactions. A key event in this process is the sperm acrosome reaction, a calcium-dependent secretory event that must be completed prior to fusion with eggs. It is now understood that sperm contact with the egg's zona pellucida coat results in the activation of sperm calcium channels and that the resulting influx of calcium acts to trigger acrosome reactions. The calcium channels that mediate zona pellucida-evoked calcium entry into sperm provide new targets for the design of contraceptive agents. This study provides the first steps towards the design of channel-based contraceptive agents. T-type calcium channels have been identified in sperm and mediate acrosome reactions, thus setting the stage for the design of sperm-specific channel antagonists and the assessment of their utility as inhibitors of fertilization.
The specific aims are: 1) to design sperm specific channel antagonists based on a systematic structure-activity analysis of classes of T channel antagonists; 2) to identify novel T channel blockers by screening small molecule libraries with a high throughput binding assay; 3) to identify drug targets by characterizing T channel transcripts expressed during spermatogenesis; and 4) to test putative lead compounds in a primate model.
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