- Title
- ent-Verticilide B1 Inhibits Type 2 Ryanodine Receptor Channels and is Antiarrhythmic in Casq2-/- MiceS
- Creator
- Gochman, Aaron; Do, Tri Q.; Cornea, Razvan L.; Laver, Derek R.; Johnston, Jeffrey N.; Knollmann, Bjorn C.; Kim, Kyungsoo; Schwarz, Jacob A.; Thorpe, Madelaine P.; Blackwell, Daniel J.; Ritschel, Paxton A.; Smith, Abigail N.; Rebbeck, Robyn T.; Akers, Wendell S.
- Relation
- Molecular Pharmacology Vol. 105, Issue 3, p. 194-201
- Publisher Link
- http://dx.doi.org/10.1124/molpharm.123.000752
- Publisher
- American Society for Pharmacology and Experimental Therapeutics
- Resource Type
- journal article
- Date
- 2024
- Description
- Intracellular Ca21 leak from cardiac ryanodine receptor (RyR2) is an established mechanism of sudden cardiac death (SCD), whereby dysregulated Ca21 handling causes ventricular arrhythmias. We previously discovered the RyR2-selective inhibitor ent-(1)-verticilide (ent-1), a 24-membered cyclooligomeric depsipeptide that is the enantiomeric form of a natural product (nat-(-)-verticilide). Here, we examined its 18-membered ring-size oligomer (ent-verticilide B1; “ent-B1”) in RyR2 single channel and [3H]ryanodine binding assays, and in Casq2-/- cardiomyocytes and mice, a gene-targeted model of SCD. ent-B1 inhibited RyR2 single channels and RyR2-mediated spontaneous Ca21 release in Casq2-/- cardiomyocytes with sub-micromolar potency. ent-B1 was a partial RyR2 inhibitor, with maximal inhibitory efficacy of less than 50%. ent-B1 was stable in plasma, with a peak plasma concentration of 1460 ng/ml at 10 minutes and half-life of 45 minutes after intraperitoneal administration of 3 mg/kg in mice. In vivo, ent-B1 significantly reduced catecholamine-induced ventricular arrhythmias in Casq2-/- mice in a dose-dependent manner. Hence, we have identified a novel chemical entity – ent-B1 – that preserves the mechanism of action of a hit compound and shows therapeutic efficacy. These findings strengthen RyR2 as an antiarrhythmic drug target and highlight the potential of investigating the mirror-image isomers of natural products to discover new therapeutics.
- Subject
- cardiac ryanodine receptor (RyR2); sudden cardiac death (SCD); mice; therapeutic efficacy; SDG 3; Sustainable Development Goals
- Identifier
- http://hdl.handle.net/1959.13/1504533
- Identifier
- uon:55548
- Identifier
- ISSN:0026-895X
- Language
- eng
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