Sudden Cardiac Death (SCD) caused by ventricular tachycardias and fibrillation (VT/VF) is a major world-wide health problem claiming the lives of some 300,000 Americans each year. Current antiarrhythmic drug (AAD) therapy to control VT/VF is largely empirical and poorly efficacious with considerable risk of proarrhythmic effects. There remains considerable unmet need for new, safe and effective AADs that specifically target the electrophysiological underpinnings of VT/VF without compromising cardiac function. Our goal is to discover and develop a small molecule antiarrhythmic drug that will address this need. Members of the Cardiovascular Research Laboratory at UCLA, Drs. Hrayr Karagueuzian and Riccardo Olcese, have recently advanced our understanding of the functional regulation of the voltage dependent calcium channel CaV1.2 by the a2d-1 subunit, and how modulation of CaV1.2 gating can reduce VT/VF triggered by early afterdepolarizations (EADs). They have also demonstrated the effect of gabapentinoids as CaV1.2 channel gating modifiers, and with this uncovered their potential therapeutic application as AADs. However, while efficacious, gabapentinoids also produce undesirable centrally mediated side effects that must be avoided in a well-tolerated chronically dosed AAD. This goal can be achieved through the design of peripherally restricted a2d-1 ligands, i.e., compounds that are orally bioavailable but not centrally penetrant, which we aim to discover. In preliminary work, Numerate has built predictive computational models for binding to a2d-1 and for being a substrate for the drug efflux pump P-glycoprotein (P-gp). These models will allow us to efficiently identify compounds that are likely to be peripherally restricted, high-affinity ligands for the gabapentinoid site on a2d-1. An initial in silico screen of 9 million commercially available compounds identified a series of compounds that are predicted to be ligands for the a2d channel subunit, and that also have a high likelihood of being peripherally restricted. We will select compounds from this screen for testing. In this SBIR grant proposal Numerate proposes to collaborate with Drs. Hrayr Karagueuzian and Riccardo Olcese at the UCLA Cardiovascular Research Laboratory in order to (1.) discover high-affinity, peripherally restricted a2d-1 ligands, and (2.) demonstrate their ability to modulate CaV1.2 channel gating and suppress EAD-triggered VT/VF in cell based assays and an isolated intact heart model.
Public Health Relevance Statement: Narrative The ultimate objective of the proposed project is to develop a small molecule drug that will address the need for a novel well-tolerated antiarrhythmic therapy for the treatment and prevention of ventricular tachycardias and fibrillation (VT/VF). By modulating gating of the voltage dependent calcium channel CaV1.2, this drug is expected to suppress early afterdepolarizations and prevent VT/VF with no adverse effects on cardiac function or centrally mediated side effects.
Project Terms: Active Biological Transport; Address; Adverse effects; Affinity; American; Amino Acid Transport System A; Amino Acids; Anti-Arrhythmia Agents; Applications Grants; Back; base; Binding; Bioavailable; Biological Assay; Blood - brain barrier anatomy; Blood Circulation; Caco-2 Cells; Calcium Channel; Cardiac; Cardiovascular system; Cause of Death; Cells; Chronic; Classification; Computer Simulation; Death, Sudden, Cardiac; design; Dizziness; Dose; Drug Efflux; efflux pump; Electrophysiology (science); Goals; Health; Heart; Human; In Vitro; in vivo; intraperitoneal; Knowledge; Laboratory Research; Ligands; Mediating; member; Memory Loss; Modeling; Mus; Muscle Cells; novel; novel therapeutics; Oral; Oryctolagus cuniculus; Oxidative Stress; P-Glycoprotein; patch clamp; Performance; Peripheral; Pharmaceutical Preparations; Pharmacotherapy; predictive modeling; prevent; Prevention; Preventive; Property; Pump; radioligand; Rattus; Regulation; Risk; screening; Sedation procedure; Series; Site; Small Business Innovation Research Grant; small molecule; Testing; Therapeutic; Ventricular; Ventricular Fibrillation; Ventricular Tachycardia; virtual; voltage; Work; Xenopus oocyte
