A single-chain derivative of the relaxin hormone is a functionally selective agonist of the G protein-coupled receptor, RXFP1.
A single-chain derivative of the relaxin hormone is a functionally selective agonist of the G protein-coupled receptor, RXFP1.
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DOI：
10.1039/c5sc04754d
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发表时间：
2016-06-01
期刊：
影响因子：
8.4
通讯作者：
Samuel CS
中科院分区：
文献类型：
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作者：
Hossain MA;Kocan M;Yao ST;Royce SG;Nair VB;Siwek C;Patil NA;Harrison IP;Rosengren KJ;Selemidis S;Summers RJ;Wade JD;Bathgate RAD;Samuel CS
松弛素激素的单链衍生物可改善纤维化且无副作用。人类基因 2 松弛素（H2 松弛素）是一种多效性激素，具有强大的血管舒张和抗纤维化特性，这导致其经过临床评估并被 FDA 临时批准用于治疗急性心力衰竭。 H2 松弛素的多种作用是通过其同源 G 蛋白偶联受体 (GPCR)、松弛素家族肽受体 (RXFP1) 介导的，从而刺激包括环磷酸腺苷 (cAMP) 和细胞外信号调节激酶 (ERK)1/2 在内的细胞信号传导途径组合。然而，其复杂的双链（A 和 B）、富含二硫键的胰岛素样结构限制了其易于制备、可用性和可负担性。此外，其对 cAMP 信号传导的强烈激活可能是导致所报告的有害肿瘤促进作用的原因，这可能会阻碍该药物长期用于治疗人类疾病。在这里，我们报告了 H2 松弛素 B 链类似物 B7-33 的设计和合成，该类似物被证明可以与 RXFP1 结合，并在内源表达 RXFP1 的细胞中优先激活 pERK 通路（而不是 cAMP）。因此，B7-33 代表复合体 GPCR RXFP1 的第一个功能选择性激动剂。重要的是，这种小肽激动剂可预防或逆转三种临床前啮齿动物心脏或肺部疾病模型中的器官纤维化和功能障碍，其效力与 H2 松弛素相似。 B7-33 强大的抗纤维化作用背后的分子机制涉及其激活 RXFP1-血管紧张素 II 2 型受体异二聚体，诱导 pERK1/2 和胶原蛋白降解酶基质金属蛋白酶 (MMP)-2 的选择性下游信号传导。此外，与 H2 松弛素相反，B7-33 不会促进体内前列腺肿瘤生长。我们的结果代表了第一个已知的例子，将双链环状胰岛素样肽最小化为单链线性肽，保留了有效的有益激动作用。
A single-chain derivative of the relaxin hormone ameliorates fibrosis without side-effects. Human gene-2 relaxin (H2 relaxin) is a pleiotropic hormone with powerful vasodilatory and anti-fibrotic properties which has led to its clinical evaluation and provisional FDA approval as a treatment for acute heart failure. The diverse effects of H2 relaxin are mediated via its cognate G protein coupled-receptor (GPCR), Relaxin Family Peptide Receptor (RXFP1), leading to stimulation of a combination of cell signalling pathways that includes cyclic adenosine monophosphate (cAMP) and extracellular-signal-regulated kinases (ERK)1/2. However, its complex two-chain (A and B), disulfide-rich insulin-like structure is a limitation to its facile preparation, availability and affordability. Furthermore, its strong activation of cAMP signaling is likely responsible for reported detrimental tumor-promoting actions that may preclude long-term use of this drug for treating human disease. Here we report the design and synthesis of a H2 relaxin B-chain-only analogue, B7-33, which was shown to bind to RXFP1 and preferentially activate the pERK pathway over cAMP in cells that endogenously expressed RXFP1. Thus, B7-33 represents the first functionally selective agonist of the complex GPCR, RXFP1. Importantly, this small peptide agonist prevented or reversed organ fibrosis and dysfunction in three pre-clinical rodent models of heart or lung disease with similar potency to H2 relaxin. The molecular mechanism behind the strong anti-fibrotic actions of B7-33 involved its activation of RXFP1-angiotensin II type 2 receptor heterodimers that induced selective downstream signaling of pERK1/2 and the collagen-degrading enzyme, matrix metalloproteinase (MMP)-2. Furthermore, in contrast to H2 relaxin, B7-33 did not promote prostate tumor growth in vivo. Our results represent the first known example of the minimisation of a two-chain cyclic insulin-like peptide to a single-chain linear peptide that retains potent beneficial agonistic effects.