Soluble adenylyl cyclase inhibition prevents human sperm functions essential for fertilization

Abstract

Soluble adenylyl cyclase (sAC: ADCY10) is essential for activating dormant sperm. Studies of freshly dissected mouse sperm identified sAC as needed for initiating capacitation and activating motility. We now use an improved sAC inhibitor, TDI-10229, for a comprehensive analysis of sAC function in human sperm. Unlike dissected mouse sperm, human sperm are collected post-ejaculation, after sAC activity has already been stimulated. Even in ejaculated human sperm, TDI-10229 interrupts stimulated motility and capacitation, and it prevents acrosome reaction in capacitated sperm. At present, there are no non-hormonal, pharmacological methods for contraception. Because sAC activity is required post-ejaculation at multiple points during the sperm journey to fertilize the oocyte, sAC inhibitors define candidates for non-hormonal, on-demand contraceptives suitable for delivery via intravaginal devices in females.

Strategies to safely target widely expressed soluble adenylyl cyclase for contraception

“…Consistent with its biochemical activity profile, sAC is most abundantly expressed in male germ cells (Buck et al, 1999;Sinclair et al, 2000); however, sAC is also widely expressed at lower levels in somatic tissues (Buck et al, 1999;Geng et al, 2005). sAC-generated-cAMP has many functions that are distinct from tmAC-generated-cAMP (Wiggins et al, 2018;Ostrom et al, 2022); including motility and capacitation of sperm (Esposito et al, 2004;Hess et al, 2005;Akbari et al, 2019;Balbach et al, 2021), and regulation of liver inflammation and fibrosis (Wang et al, 2020), pH homeostasis (Tresguerres et al, 2010), oxidative phosphorylation (Acin-Perez et al, 2009;Di Benedetto et al, 2013;Lefkimmiatis et al, 2013), lysosomal function (Rahman et al, 2016), ciliary beating frequency (Schmid et al, 2007;Chen et al, 2014), glucose homeostasis (Zippin et al, 2013;Holz et al, 2014), and intraocular pressure (Lee et al, 2011;Gandhi et al, 2017).…”

“…A subset of the physiological functions ascribed to sAC have therapeutic implications (Wiggins et al, 2018). Chief among these is sAC's role in male fertility (Esposito et al, 2004;Hess et al, 2005;Akbari et al, 2019;Balbach et al, 2021). sAC, specifically isoforms containing both C1 and C2 domains (Hess et al, 2005), is most abundant in testis and sperm and is essential for sperm to fertilize an egg.…”

“…These changes are essential for sperm to pass through the cervix to leave the inhospitable environment of the vagina and enter the permissive environment of the uterus (Visconti et al, 1995;Visconti et al, 2002;Suarez and Pacey, 2006;Buffone et al, 2014;Balbach et al, 2018). sAC's essential role in male reproduction has been validated genetically (Esposito et al, 2004;Hess et al, 2005;Akbari et al, 2019;Balbach et al, 2021) and pharmacologically (Hess et al, 2005;Mannowetz et al, 2012;Ramos-Espiritu et al, 2016;Balbach et al, 2021;Ferreira et al, 2021) in both mice and men. Two different strains of sAC knockout (KO) mice show male-specific sterility; their sperm are immotile and unable to fertilize an oocyte in vitro (Esposito et al, 2004;Hess et al, 2005;Xie et al, 2006;Chen et al, 2013).…”

Transforming Academic Drug Discovery

“…[24] The availability of TDI-10229 opened a path for an effective oral contraceptive strategy for episodic contraceptive use; such a pill would provide on demand male (or female) reversible contraception. [25]…”

“…Conversion of a weakly active screening lead, LRE1, [23] yielded the orally active, highly selective, and potent sAC inhibitor TDI‐10229 [24] . The availability of TDI‐10229 opened a path for an effective oral contraceptive strategy for episodic contraceptive use; such a pill would provide on demand male (or female) reversible contraception [25] …”