NMR study of the interaction of cardiotoxic drugs with ion channels in their membrane environment

长QT综合征（LQTS）是一种心肌异常，其特征是心电图上Q波和T波复极间隔延长。该综合征由先天性或药物性心肌细胞膜钾通道障碍引起，可导致室性心律失常和心源性猝死。在过去的几十年里，许多导致长QT的处方药已经退出市场，许多其他药物也因为同样的原因未能获得监管部门的批准。一些仍然可用的药物被迫贴上警告标签。这些非抗心律失常化合物具有不同的化学结构，属于不同的药理学类别（抗生素、抗组胺药等）。许多延长QT间期的药物都是以治疗剂量延长QT间期的。重要的是，几乎所有药物诱导的LQTS病例都是由于心脏人类乙醚相关基因（hERG）钾跨膜通道的阻断。因此，药物设计中最大的挑战之一是精心设计不与hERG通道结合或仅与hERG通道轻微结合的活性物质。我们的目标是更好地了解药物诱导的hERG钾通道阻断导致LQTS。目前，对通道阻断的构效关系以及通道内部和周围（脂膜附近）的相互作用位点知之甚少。利用固态核磁共振（SS-NMR）和互补的生物物理技术，确定决定药物- herg通道相互作用的分子特征和结合位点的位置，可以提高我们对药物作用的认识，并有助于预测其毒性。

Long QT syndrome (LQTS) is a cardiac muscle abnormality characterized by a prolongation of the repolarization interval between Q and T waves on the electrocardiogram. This syndrome is caused either by congenital or drug-induced disorders of potassium channels localized in the myocardium cell membranes, and can lead to ventricular arrhythmia and sudden cardiac death. A number of prescription medications inducing long QT have been withdrawn from the market over the past decades, and numerous other drugs have failed the regulatory approval for the same reason. Several drugs still available are forced to carry a warning label. These non-antiarrhythmic compounds have diverse chemical structures and belong to different pharmacological classes (antibiotics, antihistamines, etc). Many medications that prolong the QT interval do so at therapeutic doses. Importantly, virtually all cases of drug-induced LQTS are due to the blockade of the heart human ether-a-go-go-related-gene (hERG) potassium transmembrane channel. One of the greatest challenges in drug design, is, thus, the elaboration of active substances that do not or only slightly bind to hERG channels. Our goal is to better understand the drug-induced blockade of hERG potassium channels causing LQTS. At present, little is known of the structure-activity relationship of the channel blockade or the interaction site(s) inside and around (lipid membrane vicinity) the channel. The determination of molecular characteristics that dictate drug-hERG channel interactions and the location of the binding site(s), using solid-state nuclear magnetic resonance (SS-NMR) and complementary biophysical techniques, could improve our knowledge of drug action and help in predicting their toxicity.