# Development of Ryanodine Receptor 2 Selective Probes

> **NIH NIH F31** · VANDERBILT UNIVERSITY · 2021 · $22,682

## Abstract

PROJECT SUMMARY
 Ryanodine Receptor 2 (RyR2) mutations that result in dysregulated RyR2-mediated
calcium release are associated with a variety of cardiovascular diseases. As a result, several
small molecule probes have been used in the study and treatment of cardiac diseases through
the targeting of RyR calcium channels. Flecainide, tetracaine, and dantrolene, the most
common of these small molecule probes, are not without problems. Flecainide, for example, is
contra-indicated in patients with structural heart defects or heart failure. Furthermore, selectivity
of specific RyR isoforms (RyR1, RyR2, or RyR3) is rare, and to date, an RyR2-selective probe
does not exist. New probes to selectively modulate RyR2 would be of great use both
therapeutically and as tools to better understand the function of RyR2 and the mechanism of
intracellular calcium flux.
 This proposal focuses on the development of a new class of antiarrhythmic agents using
the hit compound discovered in the Johnston lab, ent-verticilide – the non-natural enantiomer of
the natural product (–)-verticilide. This cyclic oligomeric depsipeptide is a potent and selective
inhibitor of RyR2-mediated calcium release in mammals while the natural verticilide is inactive.
We aim to use a structure-based design approach to help clarify the interaction of ent-
verticilide with RyR2. This approach may lead to new findings in our search for potent,
selective modulators of RyR2 for the treatment of cardiac disease. Our screening will be
grounded first in the well-defined RyR2-mediated spontaneous calcium release assay. We aim
to include both discrete collections of ring-size congeners and ‘unnatural’ enantiomers, two
underexplored variables in natural-product based therapeutic development, to screen against
the target (RyR2), potentially leading to new probes. We also propose to use ent-verticilide in
pharmacological studies to determine ADME, while advancing the understanding of the
mechanism of action and RyR2 function. Our approach is well suited towards the ultimate
goals of both developing a potent, selective inhibitor of RyR2 as well as working towards
defining the mechanism of action of ent-verticilide to treat cardiac arrythmias.

## Key facts

- **NIH application ID:** 10224640
- **Project number:** 5F31HL151125-02
- **Recipient organization:** VANDERBILT UNIVERSITY
- **Principal Investigator:** Abigail Smith
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $22,682
- **Award type:** 5
- **Project period:** 2020-04-01 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10224640

## Citation

> US National Institutes of Health, RePORTER application 10224640, Development of Ryanodine Receptor 2 Selective Probes (5F31HL151125-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10224640. Licensed CC0.

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