Four CatSper genes (CatSpers1-4) are required for hyperactivated motility, normal motility over long durations, and fertility in mice. These genes encode the 4 subunits that comprise the heterotetrameric Ca2+-selective ion channel pore mediating ICatSper. Two novel proteins associate with the CatSper channel; CatSperβ and CIB12.The overall objective of this project is to identify small molecule antagonists of CatSper that would be suitable for oral delivery as contraceptive agents. Ion channels make excellent drug targets;
1. Using the accessory proteins, CatSperβ and CIB12, develop conditions for surface expression of the human CatSper1-4 channel subunits to the cell surface of cell lines, and verify that these proteins yield CatSper currents in cell lines.
2. Develop high-throughput Ca2+ imaging for screening compounds. Develop secondary screens with human sperm to verify hits, including direct electrophysiological recordings of mature, capacitated human spermatozoa.
3. Develop structure-activity relations of these molecules to find a lead candidate molecule. Determine adsorption, distribution, metabolism and excretion (ADME), toxicology for a new chemical entity (NCE), genotoxicity, safety pharmacology, and systems evaluation sufficient for an FDA IND application
