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 Casq2 -/- 小鼠的 2 型 Ryanodine 受体通道并具有抗心律失常作用。
DOI：
10.1124/molpharm.123.000752
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发表时间：
2024
影响因子：
3.6
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;Ritschel,PaxtonA;Smith,AbigailN;Rebbeck,RobynT;Akers,WendellS;Cornea,RazvanL;Laver,DerekR;Johnston,JeffreyN;Knollmann,BjornC
Ca 2+从心脏ryanodine受体（RyR2）泄漏是心源性猝死（SCD）的一个既定机制，其中Ca 2+处理失调导致室性心律失常。我们之前发现了ryr2选择性抑制剂ent-(+)-verticilide (ent-1)，这是一种24元环寡聚沉积肽，是天然产物（nat-(-)-verticilide）的对映体形式。在这里，我们在ca2 +火花试验、[3h] ryanodine结合试验、Casq2-/-心肌细胞和小鼠（一种基因靶向SCD模型）中检测了其18元环大小的低聚物（ent-verticilide B1；“ent-B1”）。nt- b1以低微摩尔效抑制ca2 +火花和[3h] ryanodine结合，并以亚微摩尔效抑制ryr2介导的Casq2-/-心肌细胞自发ca2 +释放。ent-B1是部分RyR2抑制剂，最大抑制效果小于50%。ent-B1在小鼠血浆中稳定，腹腔给药3 mg/kg后10 min血药浓度峰值为1460 ng/ml，半衰期为45 min。3 mg/kg和30 mg/kg ent-B1均可显著降低Casq2-/-小鼠儿茶酚胺引起的室性心律失常。因此，我们已经确定了一种新的化学实体- b1，它保留了击中化合物的作用机制并显示出治疗效果。这些发现加强了RyR2作为抗心律失常药物靶点的作用，并强调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.