Engineering and targeting the sperm-specific calcium channel catsper for contraception

The National Institute of Child Health and Human Development awarded Yale University $1,574,349 on February 1, 2026, under the Child Health and Human Development Extramural Research program (CFDA 93.865 / R33HD114344) to develop CatSper modulators that inhibit human sperm function as a non-steroidal male contraceptive target.

The award funds research to engineer and characterize the sperm-specific calcium channel CatSper for drug development, addressing the unmet need for male contraceptive options beyond vasectomy and condoms. Yale's principal investigator will perform high-throughput screening and functional studies on chimeric CatSper channels, including biophysical and functional characterization, molecular dynamics studies to identify drug binding sites, and development of primary and secondary screening assays that measure CatSper activity in high-throughput modes. The R33 phase will focus on lead optimization to identify potent and selective human CatSper inhibitors.

Western University of Health Sciences serves as a sub-recipient, delivering computational biophysics and drug design work led by co-investigator Dr. Luo. This work includes molecular dynamics simulations to identify potential drug binding sites using existing non-selective CatSper inhibitors and virtual screening to support lead identification and optimization across both R61 and R33 phases.

Performance occurs in New Haven, Connecticut, with a period of performance running through January 31, 2029. The assistance type is a Project Grant. Sub-award actions to Western University of Health Sciences are dated May 10, 2024, and May 20, 2026.

Abstract

The high rate of unplanned pregnancies suggests that currently available contraceptive methods are not effectively meeting the needs of women. In addition, contraceptive options for men are limited to vasectomy and condoms, leaving a significant unmet need for contraception. Our long-term goal is to develop a non-steroidal, effective contraceptive that provides a more comprehensive approach to birth control. We propose that the sperm-specific catsper calcium (CA2+) channel is an ideal target for the development of such a new class of contraceptives that has no negative side effects in either men or women, as the catsper channel is a validated target required for sperm capacitation and male fertility in both mice and humans. Drug inhibition of catsper at the post-testicular and pre-fertilization stages would work without off-target side effects due to its post-meiotic expression in male germ cells and functional divergence from other calcium channels. The recently solved struc- tures of catsper highlight its high accessibility in the cell membrane, allowing the study of the mechanism of action and reversible contraceptives. However, the inability to reconstitute the channel in vitro has been a BOT- tleneck in the development of drugs that directly target the catsper channel. We have recently overcome this hurdle by creating chimeric catsper channels that heterologously express functional channels. Using this new tool, the overall goal here is to ultimately develop catsper modulators that inhibit human sperm function. To this end, in R61 phase, we will perform in-depth biophysical and functional characterization of these novel chimeric channels and do molecular dynamics studies to gain new insights (aim 1) and develop the necessary assays for primary and secondary screening that measure catsper activity in high-throughput modes (aim 2). In the R33 phase, we will perform high-throughput screening for catsper inhib- itors as well as virtual screening (aim 3), profile the identified hits, establish preliminary structure-activity rela- tionships and perform the secondary screening (aim 4), and test the selected compounds on human sperm function (aim 5). In the immediate term, successful completion of these aims will provide small molecule hits for human catsper that can be used for iterative lead generation. In the long term, the leads and knowledge gener- ated will ultimately lead to the development of an innovative class of contraceptives targeting catsper and sperm capacitation with a mechanisms of action foundation.