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

长QT综合征(LQTS)是一种以心电图上Q波和T波的复极间期延长为特征的心肌异常。这种综合征是由先天性或药物引起的位于心肌细胞膜上的钾通道紊乱引起的，可导致室性心律失常和心脏性猝死。在过去的几十年里，许多导致QT延长的处方药已经从市场上撤出，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。几种仍可获得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，属于不同的药理类别(抗生素、抗组胺药物等)。许多延长QT间期的药物都是在治疗剂量下这样做的。重要的是，几乎所有药物诱导的LQTS都是由于心脏人类乙醚-GO-GO相关基因(HERG)钾离子跨膜通道的阻断。因此，药物设计中最大的挑战之一是精制不与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的机制。目前，对通道阻滞剂的构效关系以及通道内和周围(脂膜附近)的相互作用部位(S)知之甚少。使用固体核磁共振和互补生物物理技术来确定药物-HERG通道相互作用的分子特征和结合位点(S)的位置，可以提高我们对药物作用的了解，并有助于预测它们的毒性。

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 A number of prescription medications inducing long QT have been withdrawn from the market over the past decades, and numerous other drugs have failed the regulatory approval for the same reason.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.