On-demand male contraception via acute inhibition of soluble adenylyl cyclase

Abstract

Nearly half of all pregnancies are unintended; thus, existing family planning options are inadequate. For men, the only choices are condoms and vasectomy, and most current efforts to develop new contraceptives for men impact sperm development, meaning that contraception requires months of continuous pretreatment. Here, we provide proof-of-concept for an innovative strategy for on-demand contraception, where a man would take a birth control pill shortly before sex, only as needed. Soluble adenylyl cyclase (sAC) is essential for sperm motility and maturation. We show a single dose of a safe, acutely-acting sAC inhibitor with long residence time renders male mice temporarily infertile. Mice exhibit normal mating behavior, and full fertility returns the next day. These studies define sAC inhibitors as leads for on-demand contraceptives for men, and they provide in vivo proof-of-concept for previously untested paradigms in contraception; on-demand contraception after just a single dose and pharmacological contraception for men.

Sperm Toolbox – A selection of small molecules to study human spermatozoa

“…Recently, the application of advanced technologies has helped to move the human fertility field forward, revealing new potential targets for both contraception and fertility, and new compounds as contraceptive candidates (reviewed by (Anderson and Johnston, 2023;Service et al, 2023). A key part of this effort is the development of mechanistic insight and drug candidates that affect the behaviour and properties of human spermatozoa (Balbach et al, 2023;Carlson et al, 2022;Faber et al, 2023;Hau et al, 2022). Towards this end, we have recently developed an automated live human sperm phenotypic, targetagnostic screening platform that can screen 1000s of compounds and identify positive and negative modifiers of sperm function (Gruber et al, 2020;Gruber et al, 2022).…”

“…This work represents the first version of the STB. Future revisions could contain newly published compounds modulating functions in spermatozoa e.g., a sAC inhibitor TDI-11861 (Balbach et al, 2023), a CatSper inhibitor RU1968 (Schierling et al, 2023), a SLO3 inhibitor (Lyon et al, 2023) or other contributions from the research community. In addition, the STB could present an important resource for testing and benchmarking newly developed drug screening assay.…”

Male Contraception

“…83 Recently, it was reported that a similar compound induced reversible motility defects in sperm that prevented fertility in mice when dosed intraperitoneally. 84 Inhibition of sAC may have promised as an “on-demand” contraceptive for men.…”

Scaffold Hopping and Optimization of Small Molecule Soluble Adenyl Cyclase Inhibitors Led by Free Energy Perturbation

“…sAC, a non-membrane bound protein, is found within the cytosol and in several microdomains located inside organelles. ,, In biological systems, CO 2 is maintained in a pH-dependent equilibrium with bicarbonate (HCO 3 – ), and as a result, sAC acts as the nature’s physiological CO 2 /HCO 3 – /pH sensor. , cAMP, produced by sAC in response to changes in CO 2 /HCO 3 – /pH, has been linked to multiple biological functions, such as insulin release from pancreatic β-cells, lysosomal acidification, and regulation of intraocular eye pressure, , in addition to controlling the motility and capacitation of sperm . In regulating these biological functions, sAC is a promising drug target, with sAC inhibitors having several potential therapeutic applications. − This group has recently disclosed results describing biological application of a potent sAC inhibitor. − …”