Targeting the sAC, Male Birth Control May Soon Become a Reality

The family planning industry is severely lacking in reliable and realistic male birth control options. In fact, there have been no new FDA-approved reversible methods of male birth control since the invention of the condom in the 1850s. However, recent studies indicate the concept of male contraception is no longer as radical as it once was, with several multinational surveys indicating that more than half of male participants would take birth control if available. Luckily, for those men, several emerging non-hormonal and hormonal male birth control options may see FDA approval in the coming years.

The Biological Role of sAC in Fertilization

In mammals, bicarbonate-regulated soluble adenylyl cyclase (sAC) is one of two families of adenylyl cyclase that produces cyclic AMP (cAMP), an important signaling molecule in the body. sAC plays a vital role in sperm capacitation, a series of physiological changes that allows sperm to fuse with and fertilize an egg. Sperm is produced in the testicles and then stored in the cauda epididymis under a tightly regulated bicarbonate concentration of around 5 mM. During ejaculation, sperm mixes with semen, which has a much higher bicarbonate concentration of approximately 25 mM. Exposure to these high bicarbonate levels activates sAC in the sperm cells and begins a signaling cascade resulting in sperm capacitation. The increase in bicarbonate concentration in the sperm environment during ejaculation emphasizes the need for sAC in the fertilization capacity of sperm. Studies from as early as 2004 reported sAC knockout mice were sterile and produced sperm displaying significant defects in motility.

TDI-11861: A Novel On-Demand Contraceptive

One such option includes an inhibitor of soluble adenylyl cyclase (sAC), which could be the first on-demand male contraceptive in history. After 20 years, a viable method has been developed: an inhibitor of sAC called TDI-11861. Developed by researchers at the Tri-Institutional Therapeutics Discovery Institute, TDI-11861 inhibits sAC activity by binding to two different sites on the enzyme. The first site that TDI-11861 blocks is the bicarbonate binding pocket of sAC. This prevents enzyme activation when exposed to the high bicarbonate concentration during ejaculation, subsequently arresting sperm capacitation. TDI-11861 also binds to the active site of sAC, inhibiting cAMP formation and downstream signaling.

Experimental Efficacy and Results

When tested in vitro using mouse and human sperm cells, TDI-11861 was found to lower intracellular cAMP levels, decrease sperm flagellar beat frequency, stop the sperm from “swimming,” and prevent the fusion of the sperm with the egg plasma membrane during fertilization. Not only is TDI-11861 effective in preventing pregnancy, but so far it is outperforming every known method of birth control on the market. When 52 male mice were injected with the compound and paired with reproductively mature females from 30 minutes to 2.5 hours post-injection, there were zero pregnancies. In other words, TDI-11861 demonstrated a contraceptive efficacy of 100% for up to 2.5 hours, higher than the most effective female birth control (the implant) which is about 99% effective, and much higher than the most common female birth control (the oral contraceptive pill) which is about 91% effective.

The following table illustrates the comparative efficacy of the compound against traditional methods mentioned in the material:

Although the efficacy of TDI-11861 decreases to about 91% at 3 hours post-injection, the drug’s effectiveness is still on par with the aforementioned female birth control options.