ARumenamides: A novel class of potential anti-arrhythmic compounds.

Abstract

Loss-of-function mutations (LoF) in cardiac voltage-gated sodium channels (Nav1.5) are arrhythmogenic and cause, for example, Brugada syndrome. However, few attempts have been made to target LoF. A major impediment for the advancement of LoF therapeutics is the tendency for compounds to occlude the Nav1.5 central pore. This caveat in anti-LoF drug development may be mitigated with compounds that stabilize the activated state in Nav1.5 by binding to other sites besides the pore. We hypothesized that a novel family of compounds, called ARumenamides (ARs), with high affinity for the fenestrations would potentially reduce pore block. Six ARs,AR-051, AR-189, AR-674, AR-802, AR-807, and AR-811, were docked against a homology model of Nav1.5 built on NavAb and rNav1.5. Based on the virtual docking results, these ARs have a high affinity for Domain III-IV and Domain VI-I fenestrations. Upon functional characterization, a trend was observed in the effects of the six ARs on INa. An inverse correlation was established between the aromaticity of the AR's functional moieties and compound block. Due to its aromaticity, AR-811 blocked INa the least compared with other aromatic ARs, which also decelerated fast inactivation onset. AR-674, with its aliphatic functional group, significantly suppresses INa and enhances use-dependence in Nav1.5. AR-802 and AR-811 decelerated fast inactivation kinetics in Brugada/Long-QT syndrome mutant, E1784K, without affecting peak or late INa. The ARs we discovered seem to target LoF in Nav1.5 by preferentially occluding the fenestrations. We predict that bulkier and aromatic side groups have higher affinity for the hydrophobic milieu of the fenestrations, remaining there rather than in the central pore. Future refinements of AR compound structures and additional validation by molecular dynamic simulations and screening against more Brugada variants will further support their potential benefits in treating certain LoF cardiac arrhythmias.