Molecular mechanisms and its prevention of drug-induced long QT syndrome

获得性长QT综合征大多是由常用药物阻断心脏HERG K+通道引起的。目前尚不清楚为什么如此多的结构不同的化合物阻断HERG通道，但这种不良副作用现在被认为是开发新的安全药物的主要障碍。为了确定HERG通道的高亲和力药物阻断的结构基础，确定了III类抗心律失常药物的药物结合的重要残基;维司力农（强心剂）、E-4031、多非利特和dl-索他洛尔（甲磺酰苯胺类抗心律失常药物）、尼非卡兰（非甲磺酰苯胺类抗心律失常药物）、苄普地尔和胺碘酮（多通道阻断剂）。我们将S6的单个残基（L 646-Y 667）和孔螺旋的少数残基（L 622-V625）突变为丙氨酸，基于与KcsA通道的解析晶体结构的同源性，预测这些残基排列在通道腔和内部孔区域中（Doyle等人，1998年）。维司力农与通道腔内的六个特定残基结合。该结果发表在Molecular Pharmacology（Kamiya等人，2001年）。此外，发现胺碘酮（一种抗心律失常剂）的急性应用抑制HERG电流，而胺碘酮的长期治疗降低IK（Kamiya等人，循环001）。多非利特在六个通道中引起较少的阻断，其中Ala错义突变位于孔螺旋（T623 A、S624 A和V625 A）和S6结构域（G648 A、F656 A和V659 A）。这6个残基与MK-499中报告的残基相同。除了这些突变体，Nifekalnt对1655 A的阻断作用较小。苄普地尔不能阻断除F656 A外的任何S6突变体。这些结果表明：1）除索他洛尔外，甲磺酰苯胺类药物具有共同和相同的结合位点，2）III类药物与HERG通道的不同残基结合，从而产生不同的药理作用。

Acquired long QT syndrome is most caused by block of cardiac HERG K+ channels by commonly used medications. It is unclear why so many structurally diverse compounds block HERG channels, but this undesirable side effect now is recognized as a major hurdle in the development of new and safe drugs. To determine the structural basis for high-affinity drug block of HERG channels, determined the important residues for drug binding of class III antiarrhythmic agents ; vesnarinone (cardiotonic agent), E-4031, dofetilide and dl-sotalol(a methanesulfonanilide antiarrhythmic drug), nifekalant (a non-methanesulfonanilide antiarrhythmic drug), bepridil and amiodarone (multi-channel blockers). We mutated to alanine individual residues of S6 (L646-Y667) and the few residues of the pore helix (L622-V625) predicted to line the channel cavity and inner pore regions based on homology with the solved crystal structure of the KcsA channel (Doyle et al.,1998). Vesnarinone bound to six specific residues within the channel cavity. This result was published in Molecular Pharmacology (Kamiya et al.,2001). In addition, acute application of amiodarone, an antiarrhythmic agent, was found to inhibit HERG current, whereas long-term treatment of amiodarone decreased IKs (Kamiya et al., Circulation 001). Dofetilide caused less block in six channels with Ala missense mutations located in the pore helix (T623A, S624A and V625A) and the S6 domain (G648A, F656A and V659A). These six residues are identical to those reported on MK-499. In addition to these mutants, Nifekalnt caused less block on 1655A. Bepridil did not block any of S6 mutants except F656A. These results suggest that 1)methanesulfonanilide drugs have common and identical binding sites except sotalol, 2)class III drugs binds to different residues of HERG channels, thereby producing different, pharmacological effects.