Design, characterization, and first-in-human study of the vascular actions of a novel biased apelin receptor agonist.
Design, characterization, and first-in-human study of the vascular actions of a novel biased apelin receptor agonist.
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DOI：
10.1161/hypertensionaha.114.05099
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发表时间：
2015-04
期刊：
影响因子：
--
通讯作者：
Davenport AP
中科院分区：
文献类型：
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作者：
Brame AL;Maguire JJ;Yang P;Dyson A;Torella R;Cheriyan J;Singer M;Glen RC;Wilkinson IB;Davenport AP
补充数字内容可在正文中找到。[Pyr1]apelin-13是一种内源性血管扩张剂和肌力调节剂，但在肺动脉高压和心力衰竭中下调，使apelin受体成为一个有吸引力的治疗靶点。作用于同一G蛋白偶联受体的激动剂可以被设计成稳定不同的构象状态，并作为有偏见的配体，选择性地刺激G蛋白或β-arrestin途径。我们使用分子动力学模拟apelin/受体相互作用来设计环状类似物，并确定MM07为有偏向的激动剂。在β-arrestin和内化试验(G-蛋白质非依赖性)中，MM07的效力比[Pyr1]apelin-13低2个数量级。在G蛋白依赖的大隐静脉收缩试验中，两种多肽具有相似的效价(PD2：[Pyr1]apelin-139.93±0.24；MM079.54±0.42)和最大反应，其结果是≈的MM07值为G蛋白途径的350-1300倍。在大鼠中，全身输注MM07(10-100nmol)引起的心输出量呈剂量依赖性增加，明显大于[Pyr1]apelin-13的反应。同样，在人类志愿者中，MM07使前臂血流量显著增加，呈剂量依赖性，最大扩张倍数是[Pyr1]apelin-13的两倍。此外，重复服用MM07可使前臂血流量显著增加。这些反应与偏向激动剂更有效的作用是一致的。在人的手静脉中，这两种多肽都逆转了已建立的去甲肾上腺素收缩反应，并显著增加了静脉流量。我们的结果表明，MM07作为Apelin受体的偏向激动剂可以优先刺激G蛋白途径，这可以通过选择性地刺激血管扩张和变力作用而在临床上改善疗效，但避免激活有害的β-arrestin依赖的途径。
Supplemental Digital Content is available in the text. [Pyr1]apelin-13 is an endogenous vasodilator and inotrope but is downregulated in pulmonary hypertension and heart failure, making the apelin receptor an attractive therapeutic target. Agonists acting at the same G-protein–coupled receptor can be engineered to stabilize different conformational states and function as biased ligands, selectively stimulating either G-protein or β-arrestin pathways. We used molecular dynamics simulations of apelin/receptor interactions to design cyclic analogues and identified MM07 as a biased agonist. In β-arrestin and internalization assays (G-protein–independent), MM07 was 2 orders of magnitude less potent than [Pyr1]apelin-13. In a G-protein–dependent saphenous vein contraction assay, both peptides had comparable potency (pD2:[Pyr1]apelin-13 9.93±0.24; MM07 9.54±0.42) and maximum responses with a resulting bias for MM07 of ≈350- to 1300-fold for the G-protein pathway. In rats, systemic infusions of MM07 (10-100nmol) caused a dose-dependent increase in cardiac output that was significantly greater than the response to [Pyr1]apelin-13. Similarly, in human volunteers, MM07 produced a significant dose-dependent increase in forearm blood flow with a maximum dilatation double that is seen with [Pyr1]apelin-13. Additionally, repeated doses of MM07 produced reproducible increases in forearm blood flow. These responses are consistent with a more efficacious action of the biased agonist. In human hand vein, both peptides reversed an established norepinephrine constrictor response and significantly increased venous flow. Our results suggest that MM07 acting as a biased agonist at the apelin receptor can preferentially stimulate the G-protein pathway, which could translate to improved efficacy in the clinic by selectively stimulating vasodilatation and inotropic actions but avoiding activating detrimental β-arrestin–dependent pathways.