Danegaptide

Danegaptide is a potent, selective, and orally active gap-junction modifier^[1]. Danegaptide optimizes intercellular communication in cardiac cells by regulating electrical signal transduction, thereby restoring or improving normal heart rhythm^[2]. Danegaptide can reduce the occurrence of arrhythmic events such as atrial fibrillation^[3]. Danegaptide can protect the heart from harmful stimuli like ischemia/reperfusion injury^[4].

In vitro, pretreatment of human proximal tubule epithelial cells (hPTECs) with Danegaptide (50–100nM) for 48 hours, followed by stimulation with TGFβ1 (10ng/ml), significantly blocked connexin 43 (Cx43)-mediated hemichannel activity and inhibited ATP release^[5]. Pretreatment of rat retinal vascular endothelial cells (RRECs) with Danegaptide (100nM) for 3–7 days, followed by high glucose (30mM) stimulation, significantly maintained gap junction intercellular communication (GJIC) activity^[6].

In vivo, intraperitoneal administration of Danegaptide (3mg/kg twice daily) starting from day 3 after middle cerebral artery occlusion (MCAO) and continuing for two weeks in MCAO rats significantly improved neurological behavior, increased dendritic spine density in the hippocampal CA1 and DG regions, alleviated synaptic ultrastructural damage, and upregulated the expression of synaptic plasticity markers SYN and GAP-43, promoting synaptic plasticity and neurological functional recovery after focal cerebral ischemia^[7]. Oral administration of Danegaptide (5mg/kg/day) via drinking water to Scn5a^+/- mice from 45 weeks of age until 60 weeks significantly increased the expression and Ser368 phosphorylation of cardiac connexin 43 (Cx43), prevented Cx43 mislocalization, suppressed the development of ventricular fibrosis, and reduced abnormal proliferation of cardiac fibroblasts, thereby inhibiting age-dependent myocardial fibrosis progression^[8].

References:
[1] Dhein S, Hagen A, Jozwiak J, et al. Improving cardiac gap junction communication as a new antiarrhythmic mechanism: the action of antiarrhythmic peptides. Naunyn Schmiedebergs Arch Pharmacol. 2010 Mar;381(3):221-34.
[2] Piatnitski Chekler EL, Butera JA, et al. Discovery of a class of potent gap-junction modifiers as novel antiarrhythmic agents. Bioorg Med Chem Lett. 2009 Aug 15;19(16):4551-4.
[3] Rossman EI, Liu K, Morgan GA, et al. The gap junction modifier, GAP-134 [(2S,4R)-1-(2-aminoacetyl)-4-benzamido-pyrrolidine-2-carboxylic acid], improves conduction and reduces atrial fibrillation/flutter in the canine sterile pericarditis model. J Pharmacol Exp Ther. 2009 Jun;329(3):1127-33.
[4] Hennan JK, Swillo RE, Morgan GA, et al. GAP-134 ([2S,4R]-1-[2-aminoacetyl]4-benzamidopyrrolidine-2-carboxylic acid) prevents spontaneous ventricular arrhythmias and reduces infarct size during myocardial ischemia/reperfusion injury in open-chest dogs. J Cardiovasc Pharmacol Ther. 2009 Sep;14(3):207-14.
[5] Squires PE, Price GW, Mouritzen U, et al. Danegaptide Prevents TGFβ1-Induced Damage in Human Proximal Tubule Epithelial Cells of the Kidney. Int J Mol Sci. 2021 Mar 10;22(6):2809.
[6] Kim D, Mouritzen U, Larsen BD, et al. Inhibition of Cx43 gap junction uncoupling prevents high glucose-induced apoptosis and reduces excess cell monolayer permeability in retinal vascular endothelial cells. Exp Eye Res. 2018 Aug;173:85-90.
[7] Yang K, Zhou Y, Zhou L, et al. Synaptic Plasticity After Focal Cerebral Ischemia Was Attenuated by Gap26 but Enhanced by GAP-134. Front Neurol. 2020 Aug 26;11:888.
[8] Patin J, Castro C, Steenman M, et al. Gap-134, a Connexin43 activator, prevents age-related development of ventricular fibrosis in Scn5a^+/- mice. Pharmacol Res. 2020 Sep;159:104922.

Danegaptide是一种有效的、选择性的、具有口服活性的间隙连接（gap-junction）修饰剂^[1]。Danegaptide能够通过调节心脏细胞间的电信号传导，优化心脏细胞间的通信，从而恢复或改善心脏的正常节律^[2]。Danegaptide能够减少心房颤动等心律不齐事件的发生^[3]。Danegaptide还可保护心脏免受缺血/再灌注损伤等有害刺激的作用^[4]。

在体外，Danegaptide（50-100nM）预处理人肾近端小管上皮细胞（hPTECs）48小时，随后以TGFβ1（10ng/ml）刺激，Danegaptide显著阻断连接蛋白43（Cx43）介导的半通道活性，抑制ATP释放^[5]。Danegaptide（100nM）预处理大鼠视网膜血管内皮细胞（RRECs）3-7天，随后以高葡萄糖（30mM）刺激，显著维持间隙连接细胞间通讯（GJIC）活性^[6]。

在体内，Danegaptide（3mg/kg）从大脑中动脉闭塞（MCAO）术后第3天开始腹腔注射（每日两次），持续处理MCAO大鼠两周，Danegaptide显著改善了大鼠神经行为功能，增加了海马CA1和DG区树突棘密度，减轻了突触超微结构的破坏，并上调了突触可塑性标志物SYN和GAP-43的表达，促进局灶性脑缺血后的突触可塑性与神经功能恢复^[7]。Danegaptide（5mg/kg/day）通过饮用水口服给药，用于处理从45周龄开始直至60周龄的Scn5a^+/-小鼠，Danegaptide显著增加了心脏连接蛋白43（Cx43）的表达和Ser368位点的磷酸化，并阻止了Cx43的定位异常，预防了心室纤维化的发展，并降低了Scn5a^+/-小鼠心脏成纤维细胞的异常增殖速率，抑制年龄依赖性心肌纤维化进程^[8]。