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A collaboration between Vanderbilt University professors of chemistry and medicine yielded a promising compound to treat arrhythmia from an unlikely place: the fungal natural product verticilide.
Jeffrey Johnston, Stevenson Professor of Chemistry, said the natural product isn’t active except in insects, but the synthetic mirror-image version – or enantiomer – created in his lab is potently active in mammals against ryanodine receptor type 2, whose dysfunction can cause irregular heartbeats. Currently, many patients who suffer from arrhythmia are dependent on implantable cardioverter-defibrillators to keep their hearts working properly.
Johnston worked with Bjorn Knollmann, director of the Vanderbilt Center for Arrhythmia Research and Therapeutics, to show the synthetic compound inhibited calcium leak from ryanodine receptors, thus preventing arrhythmia.
In addition to establishing potency, the team’s tests on cells and, later, mice showed that even high doses of the unnatural version caused no ill effects.
Their work appeared Feb. 21 in the Proceedings of the Natural Academies of Science in a paper titled “Unnatural verticilide enantiomer inhibits type 2 ryanodine receptor-mediated calcium leak and is antiarrhythmic.”
The next steps will be establishing pharmacological properties, and, ultimately, develop a drug that could address the underlying problem and reduce the need for defibrillator implantations.
This work was supported in part by National Institutes of Health grants T32 NS 007491, HL092097, HL138539, GM 063557, HL128044, HL124935, HL088635, and R35-HL144980; a PhRMA Foundation Postdoctoral Fellowship; NIH Postdoctoral Fellowship F32-HL140874; American Heart Association Postdoctoral Fellowship 16POST31010019; and American Heart Association Atrial Fibrillation Strategically Focused Research Network Postdoctoral Fellowship 18SFRN34110369. Ca2+ spark measurements were performed using the Vanderbilt University Medical Center Cell Imaging Shared Resource, supported by NIH Grants CA68485, DK20593, DK58404, DK59637, and EY008126.