Development of Cyclic-oligomeric Depsipeptides as Therapeutic Agents for Arrhythmogenic Heart Diseases

Abstract

Excitation-contraction coupling links electrical signals to cardiac muscle contraction via calcium-induced calcium release. It is initiated by action potentials originated from the sinoatrial node that activates L-type calcium channels in T-tubules, subsequently triggering calcium release from the sarcoplasmic reticulum through ryanodine receptor 2 (RyR2). Dysregulated RyR2 activity underlies arrhythmogenic heart diseases. Gain-of-function mutations in RyR2 cause catecholaminergic polymorphic ventricular tachycardia, while post-translational modifications in heart failure lead to leaky RyR2 channels, promoting cardiac arrhythmia and impaired contractility. As a result, RyR2 is a key therapeutic target for cardiac arrhythmia. Clinically used RyR2 inhibitors include flecainide, dantrolene, and propafenone, but their mechanisms differ. Flecainide, a dual sodium channel blocker and an open-channel RyR2 blocker, is effective in patients without structural heart disease but poses risks in ischemic conditions. In contrast, dantrolene, a close-channel RyR2 stabilizer, improves cardiac function and reduces arrhythmias in heart failure models. Since RyR2 inhibitors with different mechanisms of action are effective for different disease states, this dissertation proposes a therapeutic classification of RyR2 inhibitors based on their mode of action on RyR2 inhibitions. Class I agents block RyR2 in its open state without altering diastolic calcium leak. Class II agents stabilize the RyR2 closed state and reduce calcium leak. In addition, this dissertation also focuses on determining the mechanism of RyR2 inhibition of new chemical entities developed by our lab including cyclic oligomeric depsipeptides (CODs) and flecainide analogs. Using single-channel recording technique, I demonstrated that flecainide analogs function as open-channel blockers (Class I) while CODs act as close-channel stabilizers (Class II). These findings highlight the importance of mechanism-specific RyR2 modulation in restoring calcium homeostasis, improving cardiac function, and reducing arrhythmogenesis in genetic and structural heart diseases.