A long-acting GH receptor antagonist through fusion to GH binding protein.
A long-acting GH receptor antagonist through fusion to GH binding protein.
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DOI：
10.1038/srep35072
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发表时间：
2016-10-12
影响因子：
4.6
通讯作者：
Ross RJ
中科院分区：
文献类型：
--
作者：
Wilkinson IR;Pradhananga SL;Speak R;Artymiuk PJ;Sayers JR;Ross RJ
肢端肥大症是一种生长激素（GH）过量的人类疾病，具有相当高的发病率和死亡率。生长抑素类似物是一线药物治疗，但高达40%的患者仍无法控制该疾病。GH受体（GHR）拮抗剂治疗更有效，但需要频繁的高剂量注射。我们已经开发了一种替代技术，用于通过与GH结合蛋白连接的突变GH的翻译融合来产生长效有效的GHR拮抗剂，并测试了三种候选分子。所有分子都具有氨基酸变化（G120 R），产生竞争性GHR拮抗剂，并且我们测试了GH结合结构域（W104 A）中的氨基酸变化将增加生物活性的假设。在生物测定中，所有都是拮抗剂。在大鼠中，所有拮抗剂的终末半衰期>20小时。在家兔皮下给药后，一种变体显示终末半衰期为40.5小时。在兔子中单次皮下注射相同的变体导致IGF-I在7天内下降14%。最后：我们提供了GHR拮抗剂与其结合蛋白的融合产生长效GHR拮抗剂的概念证明，并且我们证实了在GH结合结构域中引入W104 A氨基酸改变增强拮抗剂活性。
Acromegaly is a human disease of growth hormone (GH) excess with considerable morbidity and increased mortality. Somatostatin analogues are first line medical treatment but the disease remains uncontrolled in up to 40% of patients. GH receptor (GHR) antagonist therapy is more effective but requires frequent high-dose injections. We have developed an alternative technology for generating a long acting potent GHR antagonist through translational fusion of a mutated GH linked to GH binding protein and tested three candidate molecules. All molecules had the amino acid change (G120R), creating a competitive GHR antagonist and we tested the hypothesis that an amino acid change in the GH binding domain (W104A) would increase biological activity. All were antagonists in bioassays. In rats all antagonists had terminal half-lives >20 hours. After subcutaneous administration in rabbits one variant displayed a terminal half-life of 40.5 hours. A single subcutaneous injection of the same variant in rabbits resulted in a 14% fall in IGF-I over 7 days. In conclusion: we provide proof of concept that a fusion of GHR antagonist to its binding protein generates a long acting GHR antagonist and we confirmed that introducing the W104A amino acid change in the GH binding domain enhances antagonist activity.
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