ent -Verticilide B1 inhibits type 2 ryanodine receptor channels and is antiarrhythmic in Casq2-/- mice.
ent -Verticilide B1 inhibits type 2 ryanodine receptor channels and is antiarrhythmic in Casq2-/- mice.
复制标题
ent -Verticilide B1 抑制 2 型兰尼定受体通道，并在 Casq2-/- 小鼠中具有抗心律失常作用。
DOI：
10.1101/2023.07.03.547578
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Knollmann,BjornC
中科院分区：
文献类型：
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作者：
Gochman,Aaron;Do,TriQ;Kim,Kyungsoo;Schwarz,JacobA;Thorpe,MadelaineP;Blackwell,DanielJ;Smith,AbigailN;Akers,WendellS;Cornea,RazvanL;Laver,DerekR;Johnston,JeffreyN;Knollmann,BjornC
心肌Ryanodine受体（RyR 2）的Ca 2+泄漏是心脏性猝死（SCD）的一个既定机制，其中Ca 2+处理失调导致室性心律失常。我们先前发现了RyR 2选择性抑制剂ent-（+）-verticilide（ent-1），其是天然产物（nat-（-）-verticilide）的对映体形式的24元环寡聚缩肽。在此，我们在Ca 2+火花试验、[3 H] ryanodine结合试验以及Casq 2-/-心肌细胞和小鼠（SCD的基因靶向模型）中检测了其18元环大小的寡聚体（ent-verticilide B1;“ent-B1”）。ent-B1以低微摩尔效力抑制Ca 2+火花和[3 H] ryanodine结合，并以亚微摩尔效力抑制Casq 2-/-心肌细胞中RyR 2介导的自发Ca 2+释放。ent-B1是部分RyR 2抑制剂，最大抑制效率小于50%。ent-B1在血浆中是稳定的，在小鼠中腹膜内施用3 mg/kg后，10分钟的血浆峰浓度为1460 ng/ml，半衰期为45分钟。3 mg/kg和30 mg/kg ent-B1均显著减少Casq 2-/-小鼠中儿茶酚胺诱导的室性心律失常。因此，我们已经确定了一种新的化学实体-ent-B1-，它保留了命中化合物的作用机制，并显示出治疗效果。这些发现加强了RyR 2作为抗肿瘤药物靶标的作用，并突出了研究天然产物镜像异构体以发现新疗法的潜力。
Ca 2+ leak from cardiac ryanodine receptor (RyR2) is an established mechanism of sudden cardiac death (SCD), whereby dysregulated Ca 2+ handling causes ventricular arrhythmias. We previously discovered the RyR2-selective inhibitor ent-(+)-verticilide (ent-1), a 24-membered cyclooligomeric depsipeptide that is the enantiomeric form of a natural product (nat-(-)-verticilide). Here, we examined its 18-membered ring-size oligomer (ent-verticilide B1;“ent-B1”) in Ca 2+ spark assays,[3 H] ryanodine binding assays, and in Casq2-/-cardiomyocytes and mice, a gene-targeted model of SCD. ent-B1 inhibited Ca 2+ sparks and [3 H] ryanodine binding with low micromolar potency, and RyR2-mediated spontaneous Ca 2+ release in Casq2-/-cardiomyocytes with sub-micromolar potency. ent-B1 was a partial RyR2 inhibitor, with maximal inhibitory efficacy of less than 50%. ent-B1 was stable in plasma, with a peak plasma concentration of 1460 ng/ml at 10 min and half-life of 45 min after intraperitoneal administration of 3 mg/kg in mice. Both 3 mg/kg and 30 mg/kg ent-B1 significantly reduced catecholamine-induced ventricular arrhythmia in Casq2-/-mice. Hence, we have identified a novel chemical entity—ent-B1—that preserves the mechanism of action of a hit compound and shows therapeutic efficacy. These findings strengthen RyR2 as an antiarrhythmic drug target and highlight the potential of investigating the mirror-image isomers of natural products to discover new therapeutics.