SEMINARIO “On demand contraception via acute inhibition of soluble adenylyl cyclase” por Dra. Melanie Balbach

TITULO
“On demand contraception via acute inhibition of soluble adenylyl cyclase”

DISERTANTE
Dra. Melanie Balbach
Postdoctoral Fellow
Department of Pharmacology
Weill Cornell Medicine, USA

RESUMEN
Nearly half of all pregnancies are unintended, revealing existing family planning options are inadequate. Soluble adenylyl cyclase (sAC: ADCY10) has been genetically confirmed to be essential for male fertility in mice and humans. In mice, ex vivo studies of dormant, caudal epididymal sperm demonstrated that sAC is required for initiating capacitation and activating motility. We use an improved sAC inhibitor, TDI-10229, for a comprehensive analysis of sAC function in mouse and human sperm and showed that sAC inhibitors interrupt capacitation-induced changes in ejaculated human sperm. This defines sAC inhibitors as candidates for non-hormonal, on-demand contraceptives suitable for delivery via intravaginal devices in women.

We further developed sAC inhibitors which are fast acting and exhibit long residence time on sAC protein permitting its inhibitory effect to persist after ejaculated sperm enter the inhibitor-free female reproductive tract. After a single dose of TDI-11861, male mice are temporarily infertile. Sperm function and fertility returns to normal by the next day. These studies provide in vivo proof-of-concept that pharmacological contraception for men is achievable and define sAC inhibitors as lead compounds for first-of-their-kind non-hormonal, on-demand contraceptives for men.