Unnatural verticilide enantiomer inhibits type 2 ryanodine receptor-mediated calcium leak and is antiarrhythmic

Proceedings of the National Academy of Sciences of the United States of America
Suzanne M BatisteBjörn C Knollmann

Abstract

Ca2+ leak via ryanodine receptor type 2 (RyR2) can cause potentially fatal arrhythmias in a variety of heart diseases and has also been implicated in neurodegenerative and seizure disorders, making RyR2 an attractive therapeutic target for drug development. Here we synthesized and investigated the fungal natural product and known insect RyR antagonist (-)-verticilide and several congeners to determine their activity against mammalian RyR2. Although the cyclooligomeric depsipeptide natural product (-)-verticilide had no effect, its nonnatural enantiomer [ent-(+)-verticilide] significantly reduced RyR2-mediated spontaneous Ca2+ leak both in cardiomyocytes from wild-type mouse and from a gene-targeted mouse model of Ca2+ leak-induced arrhythmias (Casq2-/-). ent-(+)-verticilide selectively inhibited RyR2-mediated Ca2+ leak and exhibited higher potency and a distinct mechanism of action compared with the pan-RyR inhibitors dantrolene and tetracaine and the antiarrhythmic drug flecainide. ent-(+)-verticilide prevented arrhythmogenic membrane depolarizations in cardiomyocytes without significant effects on the cardiac action potential and attenuated ventricular arrhythmia in catecholamine-challenged Casq2-/- mice. These findings indic...Continue Reading

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Citations

Mar 3, 2020·The Journal of Physiology·Matthew J WleklinskiBjӧrn C Knollmann
Jun 2, 2020·Frontiers in Pharmacology·Arpad Tosaki
Jan 6, 2021·Pflügers Archiv : European journal of physiology·Satadru K LahiriXander H T Wehrens
Dec 11, 2020·Circulation Research·Dmytro O KryshtalBjorn C Knollmann
Jun 8, 2021·The Journal of Organic Chemistry·Abigail N Smith, Jeffrey N Johnston
May 22, 2021·Journal of the American College of Cardiology·Silvia G PrioriJason C Kovacic
Apr 29, 2020·ACS Central Science·Maja Köhn
Dec 18, 2021·ACS Medicinal Chemistry Letters·Abigail N SmithJeffrey N Johnston

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