新型偏向 Apelin 受体激动剂血管作用的设计、表征和首次人体研究,Hypertension

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新型偏向 Apelin 受体激动剂血管作用的设计、表征和首次人体研究
Hypertension ( IF 6.9 ) Pub Date : 2015-04-01 , DOI: 10.1161/hypertensionaha.114.05099
Aimee L. Brame ₁ , Janet J. Maguire ₁ , Peiran Yang ₁ , Alex Dyson ₁ , Rubben Torella ₁ , Joseph Cheriyan ₁ , Mervyn Singer ₁ , Robert C. Glen ₁ , Ian B. Wilkinson ₁ , Anthony P. Davenport ₁

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[Pyr1]apelin-13 是一种内源性血管扩张剂和正性肌力药，但在肺动脉高压和心力衰竭中下调，使 apelin 受体成为有吸引力的治疗靶点。可以设计作用于相同 G 蛋白偶联受体的激动剂以稳定不同的构象状态，并作为偏向配体发挥作用，选择性地刺激 G 蛋白或 &bgr;-抑制蛋白通路。我们使用 apelin/受体相互作用的分子动力学模拟来设计环状类似物，并将 MM07 鉴定为偏向激动剂。在 &bgr;-arrestin 和内化分析（不依赖 G 蛋白）中，MM07 的效力比 [Pyr1]apelin-13 低 2 个数量级。在 G 蛋白依赖性大隐静脉收缩试验中，两种肽具有相当的效力（pD2:[Pyr1]apelin-13 9.93±0.24；MM07 9.54±0。42) 和最大响应，MM07 的结果偏差为 G 蛋白途径的 ≈350 到 1300 倍。在大鼠中，MM07 (10-100nmol) 的全身输注导致心输出量的剂量依赖性增加，其显着大于对 [Pyr1]apelin-13 的反应。类似地，在人类志愿者中，MM07 产生了显着的剂量依赖性前臂血流量增加，最大扩张倍数与 [Pyr1]apelin-13 相同。此外，重复剂量的 MM07 可重复增加前臂血流量。这些反应与偏向激动剂的更有效作用一致。在人手静脉中，两种肽都能逆转既定的去甲肾上腺素收缩反应并显着增加静脉流量。

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Design, Characterization, and First-In-Human Study of the Vascular Actions of a Novel Biased Apelin Receptor Agonist

[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 &bgr;-arrestin pathways. We used molecular dynamics simulations of apelin/receptor interactions to design cyclic analogues and identified MM07 as a biased agonist. In &bgr;-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 &bgr;-arrestin–dependent pathways.

更新日期：2015-04-01

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