Discovering the chemical CatSper interactome: Subunit-targeted hit generation for the development of non-hormonal male contraceptives

• Applicant: Dr. Wenxin Felix Zhu
• Subject Area: Pharmacy
• Term: since 2026
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 579715750

With approximately 50% of pregnancies worldwide being unintended, and nearly all modern contraceptive methods targeting the female reproductive system, there is a significant unmet global need for safer and more user-friendly contraceptive options. Male contraceptive strategies are being increasingly explored, which target sperm proteins essential for fertility. One such target is CatSper, a sperm-specific ion channel that regulates hyperactivation. Hyperactivation is a characteristic motility pattern required for sperm to penetrate egg cells. CatSper is genetically well-validated as essential for male fertility, and its inhibition is increasingly recognized as a promising approach for male contraception. However, pharmacological validation remains unresolved, largely due to the lack of selective small-molecule tool compounds. This research proposal aims to advance the validation of CatSper as a drug target for contraception. For a drug to be effective as a male contraceptive, it must retain target engagement after dilution in the female reproductive tract post-ejaculation. To address this, a covalent fragment library will be tested against CatSper to identify new irreversible inhibitors of sperm function. Different orthogonal assays will be used to evaluate the compound library. Among them, one assay will be developed that measures target engagement of sperm proteins by ligands in their native cellular environment. Additionally, this platform will be able to annotate respective binding sites, creating a network of the chemical CatSper interactome, displaying the chemical structure, binding site, and biological activity of newly identified CatSper ligands. Altogether, the identification of covalent, in-cellulo-active CatSper ligands, along with their respective binding sites, is expected to bear great potential for future drug discovery efforts, which target CatSper for the development of male contraceptives.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Professorin Dr. Jean-Ju Chung