Enantiomer of a fungal compound inhibits a leaky receptor channel linked to heart problems

Natural products derived from plants, fungi, and even microbes have been fruitful sources of drugs. Now research shows that their chemical mirror images may be an underexplored source of potential drugs, too.

One such compound, an enantiomer of the fungal biomolecule verticilide, shows promise as a starting point for developing compounds to treat heart arrhythmias and neurological diseases. In insects, verticilide inhibits the ryanodine receptor (RyR) channel, an intracellular calcium channel that mediates muscle contraction, which in mammals can cause heart problems when it leaks.

Scientists at Vanderbilt University screened verticilide for its ryanodine-blocking abilities in a fluorescent-cell assay, but it turned out to be a dud. Surprisingly, its mirror image lit up.

Led by Vanderbilt’s Jeffrey N. Johnston and Bjorn C. Knollmann, the team found that ent-verticilide significantly reduces the calcium leak through ryanodine receptor type 2 (RyR2) channels in cell and mouse studies (Proc. Natl. Acad. Sci. 2019, DOI: 10.1073/pnas.1816685116).

RyR2 has been implicated in Alzheimer’s disease, memory loss, seizures, and heart arrhythmias, which can be fatal. It’s one of three types of RyR channels found in the body. Current therapeutics target all RyR channels nonselectively, leading to side effects such as muscle weakness and liver toxicity. “Once I saw this activity I got very excited about it because there aren’t any potent inhibitors of this channel,” says Knollmann, whose lab focuses on heart-rhythm biology.

“We didn’t intuit that it would be this way at all,” Johnston says. In fact, they only tested the unnatural enantiomer of the natural product because it was easy to make based on chemistry previously developed in Johnston’s lab (Proc. Natl. Acad. Sci. 2016, DOI: 10.1073/pnas.1616462114). ent-Verticilide seemed like a good control molecule to add into the initial assay, he says.

Researchers should test these underexplored unnatural enantiomers for activity more often, says Scripps Research Institute synthetic chemist Ryan A. Shenvi. However, making a natural product’s enantiomer is usually more challenging than it was for verticilide, he says.

Shenvi adds that it’s “so interesting” that the unnatural enantiomer is active at the human ryanodine receptor while the natural enantiomer is active in the insect version. He wonders what molecular interactions led to that specificity. The authors say they plan to run protein-docking studies to better understand the unnatural enantiomer’s surprising activity.