The selective RyR2 inhibitor ent-verticilide suppresses atrial fibrillation susceptibility caused by Pitx2 deficiency

Kim, Kyung-Soo; Blackwell, Daniel J.; Yuen, Samantha L.; Thorpe, Madelaine P.; Johnston, Jeff N.; Cornea, Rǎzvan L.; Knollmann, Björn C.

doi:10.1016/j.yjmcc.2023.04.005

Cited by 17 publications

(8 citation statements)

References 49 publications

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“…Verticilide, a derivative of a fungal compound, is another example if a RyR2 regulator that shows therapeutic potential. Verticilide inhibits hyper-active RyR2 and has shown antiarrhythmic potential in a model of inherited arrhythmia [ 105 ], AF [ 106 ] and arrhythmogenic cardiomyopathy [ 107 ]. Given the high incidence of arrhythmia in HF patients [ 90 ], dantrolene, Rycals and verticilide present promising therapeutic avenues to explore.…”

Section: Discussionmentioning

confidence: 99%

Clustering properties of the cardiac ryanodine receptor in health and heart failure

Waddell,

Mereacre,

Alvarado

et al. 2023

Journal of Molecular and Cellular Cardiology

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Section: Discussionmentioning

confidence: 99%

Clustering properties of the cardiac ryanodine receptor in health and heart failure

Waddell,

Mereacre,

Alvarado

et al. 2023

Journal of Molecular and Cellular Cardiology

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“…Drug-like small-molecule modulators of the RyRs have been identified by serendipity, and some of these have been under consideration as inhibitors of the pathologic Ca 2+ -leak through RyR2 with potential uses as antiarrhythmics and in other clinical indications linked to hyperactive resting RyRs. , In a similar manner, we have identified the unnatural enantiomer ( ent ) of verticilide (a natural cyclic depsipeptide produced by the fungus Verticillium sp and demonstrated efficacy against atrial and ventricular arrhythmias in vivo. , Locating the RyR binding site of such drug candidates represents a major prerequisite for (a) understanding their mechanism of action and (b) their further optimization via structure-guided medicinal chemistry.…”

Section: Introductionmentioning

confidence: 91%

“…7 ) as a specific inhibitor of the RyR2 pathologic leak in nanomolar (i.e., resting) Ca demonstrated efficacy against atrial and ventricular arrhythmias in vivo. 8,9 Locating the RyR binding site of such drug candidates represents a major prerequisite for (a) understanding their mechanism of action and (b) their further optimization via structure-guided medicinal chemistry. A major hurdle in locating a small molecule bound to an RyR is the size of the RyR complex.…”

Section: ■ Introductionmentioning

confidence: 99%

RyR2 Binding of an Antiarrhythmic Cyclic Depsipeptide Mapped Using Confocal Fluorescence Lifetime Detection of FRET

Šeflová,

Schwarz,

Smith

et al. 2023

ACS Chem. Biol.

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Hyperactivity of cardiac sarcoplasmic reticulum (SR) ryanodine receptor (RyR2) Ca 2+ -release channels contributes to heart failure and arrhythmias. Reducing the RyR2 activity, particularly during cardiac relaxation (diastole), is a desirable therapeutic goal. We previously reported that the unnatural enantiomer (ent) of an insect-RyR activator, verticilide, inhibits porcine and mouse RyR2 at diastolic (nanomolar) Ca 2+ and has in vivo efficacy against atrial and ventricular arrhythmia. To determine the ent-verticilide structural mode of action on RyR2 and guide its further development via medicinal chemistry structure−activity relationship studies, here, we used fluorescence lifetime (FLT)measurements of Forster resonance energy transfer (FRET) in HEK293 cells expressing human RyR2. For these studies, we used an RyR-specific FRET molecular-toolkit and computational methods for trilateration (i.e., using distances to locate a point of interest). Multiexponential analysis of FLT-FRET measurements between four donor-labeled FKBP12.6 variants and acceptorlabeled ent-verticilide yielded distance relationships placing the acceptor probe at two candidate loci within the RyR2 cryo-EM map. One locus is within the Ry12 domain (at the corner periphery of the RyR2 tetrameric complex). The other locus is sandwiched at the interface between helical domain 1 and the SPRY3 domain. These findings document RyR2-target engagement by ent-verticilide, reveal new insight into the mechanism of action of this new class of RyR2-targeting drug candidate, and can serve as input in future computational determinations of the ent-verticilide binding site on RyR2 that will inform structure−activity studies for lead optimization.

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“…For instance, RyR2 inhibition can be achieved by repurposing dantrolene, a clinical drug used as a RyR1 inhibitor, or using ent-verticilide, which is a selective RyR2 inhibitor that suppressed AF susceptibility caused by hyperactive RyR2s. 45 Indeed, dantrolene has been shown to reduce SCRs in human atria and triggered activity in human ventricles. [46][47][48] Also, propafenone 49 and flecainide are found to act through inhibition of RyR2s when treating catecholaminergic polymorphic ventricular tachycardia.…”

Section: Interventions Targeting T-tubules and Ca 2+ Handling Effecti...mentioning

confidence: 99%

Enhanced Ca²⁺-Driven Arrhythmias in Female Patients with Atrial Fibrillation: Insights from Computational Modeling

Zhang,

Wu,

Smith

et al. 2024

Preprint

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Background and AimsSubstantial sex-based differences have been reported in atrial fibrillation (AF), with female patients experiencing worse symptoms, increased complications from drug side effects or ablation, and elevated risk of AF-related stroke and mortality. Recent studies revealed sex-specific alterations in AF-associated Ca2+dysregulation, whereby female cardiomyocytes more frequently exhibit potentially proarrhythmic Ca2+-driven instabilities compared to male cardiomyocytes. In this study, we aim to gain a mechanistic understanding of the Ca2+-handling disturbances and Ca2+-driven arrhythmogenic events in males vs females and establish their responses to Ca2+-targeted interventions.Methods and ResultsWe incorporated known sex differences and AF-associated changes in the expression and phosphorylation of key Ca2+-handling proteins and in ultrastructural properties and dimensions of atrial cardiomyocytes into our recently developed 3D atrial cardiomyocyte model that couples electrophysiology with spatially detailed Ca2+-handling processes. Our simulations of quiescent cardiomyocytes show increased incidence of Ca2+sparks in female vs male myocytes in AF, in agreement with previous experimental reports. Additionally, our female model exhibited elevated propensity to develop pacing-induced spontaneous Ca2+releases (SCRs) and augmented beat-to-beat variability in action potential (AP)-elicited Ca2+transients compared with the male model. Parameter sensitivity analysis uncovered precise arrhythmogenic contributions of each component that was implicated in sex and/or AF alterations. Specifically, increased ryanodine receptor phosphorylation in female AF cardiomyocytes emerged as the major SCR contributor, while reduced L-type Ca2+current was protective against SCRs for male AF cardiomyocytes. Furthermore, simulations of tentative Ca2+-targeted interventions identified potential strategies to attenuate Ca2+-driven arrhythmogenic events in female atria (e.g., t-tubule restoration, and inhibition of ryanodine receptor and sarcoplasmic/endoplasmic reticulum Ca²⁺-ATPase), and revealed enhanced efficacy when applied in combination.ConclusionsOur sex-specific computational models of human atrial cardiomyocytes uncover increased propensity to Ca2+-driven arrhythmogenic events in female compared to male atrial cardiomyocytes in AF, and point to combined Ca2+-targeted interventions as promising approaches to treat AF in female patients. Our study establishes that AF treatment may benefit from sex-dependent strategies informed by sex-specific mechanisms.Translational perspectiveAccumulating evidence demonstrates substantial sex-related differences in atrial fibrillation (AF), which is the most common arrhythmia, with female patients faring worse with the condition. By integrating known sex-differential components into our computational atrial cardiomyocyte model we found that female atrial cardiomyocytes in AF exhibit greater propensity to develop Ca2+-driven arrhythmia than male cardiomyocytes. Model analyses provided novel mechanistic insights and suggested strategies such as t-tubule restoration, correction of Ca2+-handling disturbances, and the combination of both, as promising approaches to treat AF in female patients. Our study uncovers and validate sex-specific AF mechanisms and inform the development of targeted anti-AF strategies.Graphical abstractSex-specific 3D spatiotemporal models of human atrial cardiomyocyte Ca2+signaling reveal a greater propensity to develop Ca2+-driven arrhythmic events in female vs male atrial cardiomyocytes in AF. Model analysis links sex-specific AF remodeling to arrhythmogenic mechanisms. AF, atrial fibrillation; SCR, spontaneous Ca2+release; CaT, cytosolic Ca2+transient; RyR2-P, phosphorylated ryanodine receptor type 2 (RyR2); CSQ, calsequestrin; LTCC, L-type Ca2+channel; PLB, phospholamban; SERCA, sarcoendoplasmic reticulum Ca2+ATPase.

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The selective RyR2 inhibitor ent-verticilide suppresses atrial fibrillation susceptibility caused by Pitx2 deficiency

Cited by 17 publications

References 49 publications

Clustering properties of the cardiac ryanodine receptor in health and heart failure

Clustering properties of the cardiac ryanodine receptor in health and heart failure

RyR2 Binding of an Antiarrhythmic Cyclic Depsipeptide Mapped Using Confocal Fluorescence Lifetime Detection of FRET

Enhanced Ca²⁺-Driven Arrhythmias in Female Patients with Atrial Fibrillation: Insights from Computational Modeling

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The selective RyR2 inhibitor ent-verticilide suppresses atrial fibrillation susceptibility caused by Pitx2 deficiency

Cited by 17 publications

References 49 publications

Clustering properties of the cardiac ryanodine receptor in health and heart failure

Clustering properties of the cardiac ryanodine receptor in health and heart failure

RyR2 Binding of an Antiarrhythmic Cyclic Depsipeptide Mapped Using Confocal Fluorescence Lifetime Detection of FRET

Enhanced Ca2+-Driven Arrhythmias in Female Patients with Atrial Fibrillation: Insights from Computational Modeling

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Enhanced Ca²⁺-Driven Arrhythmias in Female Patients with Atrial Fibrillation: Insights from Computational Modeling