Poison arrows inspire new male contraceptive, scientists report

According to scientists, a poison arrow in the quiver may let loose a very sticky nether-region massacre.

The poison in question has spattered from the tips of African weapons for centuries, rubbing out wild beasts and halting the hearts of warriors. But, according to a study in the Journal of Medicinal Chemistry, a crotch shot of an ancient toxin called “ouabain” can also take out sperm. By tweaking the poison’s chemical backbone (or scaffold), it can selectively paralyze trouser troops and prevent them from storming eggs, the authors report.

The study’s authors, led by Shameem Sultana Syeda of the University of Minnesota, are optimistic that, with further aiming, the poison’s progeny could one day strike as a safe, reversible male contraceptive.

The chemical descendants that the authors have already spawned “interfere with sperm motility and sperm hyperactivation,” they report. Thus “this novel scaffold represents an attractive chemical structure for further development of a highly specific male contraceptive,” they conclude.

For centuries, African warriors and hunters have extracted ouabain from the two eastern African plants that make it—Acokanthera schimperi and Strophanthus gratus—and slathered the poison onto their arrow heads. At such a dose, ouabain can cause twitching, convulsions, high blood pressure, rapid heart rate, and eventually cardiac arrest. In modern times, scientists have used ouabain in biomedical research and even used it as a therapy for low blood pressure and irregular heartbeats—at very low doses. But it was only recently considered a potential bane of baby batter.

Ouabain works by gunking up certain sodium-potassium channels that actively pump ions across cellular membranes. These channels, called Na,K-ATPases, contain two pieces, α and β subunits. Ouabain binds to the α unit, the catalytic business end. When it does, the channel overall stops functioning and ion concentrations in the cell get thrown out of whack. In the heart, this causes cardiac muscle cells to contract with more force than necessary, for instance.

Sinking swimmers

Sperm also use one of these channels—it helps power the tail-like flagella that sperm use to wiggle around. When the channel is knocked out, the little swimmers are dead in the water. The Na,K-ATPase α subunits in sperm are slightly different from those found in the heart and other parts of the body, though. The spunky subunits are dubbed α4—as opposed to Na,K-ATPase α1, α2, and α3 found elsewhere. The study authors hypothesized that they could tweak ouabain to strongly and specifically go after α4 over the others, thereby sparing some toxic side-effects while sinking sperm.

Syeda and her colleagues set out on crotch-adjacent chemistry by tweaking and swapping atoms and structures dangling off the sides of ouabain’s structure. Using artificial setups with the Na,K-ATPases, they found a few that could jam up α4 over the other α units. When they incubated the chemicals with rat sperm, the sperm was immobilized.

Last, the researchers fed one of the most promising chemicals to rats. The ouabain derivative didn’t have any toxic effects, and the rat produced normal levels of sperm. But the chemical caused the rodents’ sperm to be about 50-percent less mobile. In humans, such a level could interfere with fertility.

The researchers have a long, long way to go before any ouabain derivatives make it into male pill form. But they argue that the strategy is worth pursuing. It has the “advantage of blocking sperm function without affecting undifferentiated male germ cells, which allows for temporary and reversible inhibition of male fertility.”

Journal of Medicinal Chemistry, 2018. DOI: 10.1021/acs.jmedchem.7b00925  (About DOIs).