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Publication
Unnatural verticilide enantiomer inhibits type 2 ryanodine receptor-mediated
calcium leak and is antiarrhythmic.
Authors Batiste SM, Blackwell DJ, Kim K, Kryshtal DO, Gomez-Hurtado N, Rebbeck RT,
Cornea RL, Johnston JN, Knollmann BC
Submitted By Submitted Externally on 4/8/2019
Status Published
Journal Proceedings of the National Academy of Sciences of the United States of America
Year 2019
Date Published 3/1/2019
Volume : Pages 116 : 4810 - 4815
PubMed Reference 30792355
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 indicate that ent-(+)-verticilide is a potent and selective
inhibitor of RyR2-mediated diastolic Ca2+ leak, making it a molecular tool to
investigate the therapeutic potential of targeting RyR2 hyperactivity in heart
and brain pathologies. The enantiomer-specific activity and straightforward
chemical synthesis of (unnatural) ent-(+)-verticilide provides a compelling
argument to prioritize ent-natural product synthesis. Despite their general
absence in nature, the enantiomers of natural products may harbor unprecedented
activity, thereby leading to new scaffolds for probe and therapeutic
development.





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