Moreno Jonathan D, Zhu Wandi, Mangold Kathryn, Chung Woenho, Silva Jonathan R
Division of Cardiology, Department of Medicine, Washington University in St. Louis, St. Louis, Missouri.
Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, Missouri.
JACC Basic Transl Sci. 2019 Oct 28;4(6):736-751. doi: 10.1016/j.jacbts.2019.06.002. eCollection 2019 Oct.
Antiarrhythmic treatment strategies remain suboptimal due to our inability to predict how drug interactions with ion channels will affect the ability of the tissues to initiate and sustain an arrhythmia. We built a multiscale molecular model of the Na channel domain III (domain III voltage-sensing domain) to highlight the molecular underpinnings responsible for mexiletine drug efficacy. This model predicts that a hyperpolarizing shift in the domain III voltage-sensing domain is critical for drug efficacy and may be leveraged to design more potent Class I molecules. The model was therefore used to design, in silico, a theoretical mexiletine booster that can dramatically rescue a mutant resistant to the potent antiarrhythmic effects of mexiletine. Our framework provides a strategy for in silico design of precision-targeted therapeutic agents that simultaneously assesses antiarrhythmic markers of success and failure at multiple spatial and time scales. This approach provides a roadmap for the design of novel molecular-based therapy to treat myriad arrhythmia syndromes, including ventricular tachycardia, heart failure arrhythmias, and inherited arrhythmia syndromes.
由于我们无法预测药物与离子通道的相互作用将如何影响组织引发和维持心律失常的能力，抗心律失常治疗策略仍然不够理想。我们构建了一个钠通道结构域III（结构域III电压感应结构域）的多尺度分子模型，以突出负责美西律药物疗效的分子基础。该模型预测，结构域III电压感应结构域的超极化偏移对药物疗效至关重要，并且可用于设计更有效的I类分子。因此，该模型被用于在计算机上设计一种理论上的美西律增强剂，它可以显著挽救对美西律强效抗心律失常作用产生抗性的突变体。我们的框架提供了一种在计算机上设计精准靶向治疗药物的策略，该策略能在多个空间和时间尺度上同时评估抗心律失常成功和失败的标志物。这种方法为设计新型分子疗法以治疗多种心律失常综合征提供了路线图，这些综合征包括室性心动过速、心力衰竭心律失常和遗传性心律失常综合征。
