# Development of a Mirror-Image Natural Product as an Antiarrhythmic Therapeutic

> **NIH NIH R01** · VANDERBILT UNIVERSITY · 2022 · $777,069

## Abstract

Project Summary
This program focuses on the development of a new class of antiarrhythmic agents that inhibit
pathologically hyperactive RyR2, the calcium release channel in the sarcoplasmic reticulum
(intracellular) membrane. RyR2 is a validated therapeutic target in a human genetic arrhythmia
syndrome – Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT). CPVT is caused by
gain of function mutations in RyR2. RyR2 hyperactivity has also been implicated mechanistically
in several other arrhythmia disorders, but RyR2-selective inhibitors are lacking. The overarching
goal of this transdisciplinary program is the selection of antiarrhythmic clinical candidates based
on the discovery that the enantiomer of the natural product verticilide (ent-verticilide) is a potent
inhibitor of RyR2-mediated calcium release in cardiomyocytes. Preliminary data from our
laboratories includes the discovery of ent-verticilide as a potent and (the first) selective inhibitor,
in contrast to its mirror-image, natural form. These tools have already shown an antiarrhythmic
effect in CPVT animal models of disease, thereby supporting the premise that selective
therapeutics can improve our understanding of RyR2 biology. Preliminary results are also founded
upon a de novo chemical synthesis of verticilide that provides both renewable access to drug, as
well as a platform for rapid analogue development, both in support of pharmacology studies. Aim
1 describes a broader program to explore ent-verticilide's biological activity and pharmacology, at
RyR2, in cardiomyocytes, and in mouse models of disease. The goal of Aim 2 is to prepare scores
of ent-verticilide analogues that further optimize potency while retaining selectivity. The premise
is that ent-verticilide is a powerful lead whose modularity will enable the development of a
molecular picture of structure-activity relationships despite the lack of a structural picture for RyR2
due to its size and complexity. A strength of this approach is its ability to adapt to changes in the
state of the art in RyR2 structural biology, an effort to which we will contribute as well (Aim 1).
Highly potent and selective compounds will be advanced in vivo for safety and efficacy studies in
Aim 3. This program is highly collaborative and transdisciplinary in nature, and the studies will
advance a novel class of compounds never-before-used in therapeutic development. Preliminary
results have already advanced our understanding of RyR2 molecular pharmacology, and promise
new antiarrhythmic agents to improve human health.

## Key facts

- **NIH application ID:** 10372134
- **Project number:** 5R01HL151223-03
- **Recipient organization:** VANDERBILT UNIVERSITY
- **Principal Investigator:** Jeffrey Nicholas Johnston
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $777,069
- **Award type:** 5
- **Project period:** 2020-03-17 → 2024-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10372134

## Citation

> US National Institutes of Health, RePORTER application 10372134, Development of a Mirror-Image Natural Product as an Antiarrhythmic Therapeutic (5R01HL151223-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10372134. Licensed CC0.

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