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

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 A number of prescription medications inducing long QT have been withdrawn from the market over the past decades, and numerous other drugs have failed the regulatory approval for the same reason.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