Development of a long acting FGF21 analogue-albumin fusion protein and its anti-diabetic effects
Development of a long acting FGF21 analogue-albumin fusion protein and its anti-diabetic effects
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长效FGF21类似物-白蛋白融合蛋白的研制及其抗糖尿病作用
DOI：
10.1016/j.jconrel.2020.05.036
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发表时间：
2020
影响因子：
10.8
通讯作者：
Toru Maruyama# *equal contribution; #equal correspondence
中科院分区：
文献类型：
--
作者：
Hiroshi Watanabe*,#;Masako Miyahisa*;Mayuko Chikamatsu*;Kento Nishida;Yuki Minayoshi;Mei Takano;Shota Ichimizu;Yoshihiro Kobashigawa;Hiroshi Morioka;Hitoshi Maeda;Toru Maruyama# *equal contribution; #equal correspondence
成纤维细胞生长因子21（FGF 21）是一种能改善血糖和脂质代谢的类胰蛋白酶蛋白。然而，其半衰期短和不稳定性是其临床应用的瓶颈。本研究通过构建稳定的突变型FGF 21（mFGF 21：ΔHPIP，P171 G，A180 E，L118 C-A134 C，S167 A），并通过多肽连接子将其与人白蛋白（HSA）融合，以进一步发挥其药理作用。物理化学分析表明HSA-mFGF 21由完整的HSA和mFGF 21两者形成。药代动力学结果表明，HSA-mFGF 21的半衰期比FGF 21的半衰期长20倍。此外，HSA-mFGF 21持续分布在作为靶组织的脂肪组织中。使用链脲佐菌素（STZ）诱导的I型糖尿病模型小鼠（其中胰岛素分泌被抑制），HSA-mFGF 21的体内降血糖活性显示，单次静脉内施用HSA-mFGF 21迅速减轻高血糖。此时，HSA-mFGF 21增加脂肪组织中GLUT 1 mRNA的表达，而对胰岛素分泌没有任何影响。每周两次给予HSA-mFGF 21持续抑制血糖水平，并改善STZ治疗诱导的脂肪组织异常。有趣的是，HSA-mFGF 21在健康小鼠中没有显示出降血糖作用。总之，HSA-mFGF 21可能是用于治疗包括糖尿病在内的代谢紊乱的新型生物制剂。
Fibroblast growth factor 21 (FGF21) is a hormone-like protein that improves blood glucose and lipid metabolism. However, its short half-life and instability are bottlenecks to its clinical applications. In this study, to extend its pharmacological action, we created a stabilized mutant FGF21 (mFGF21:ΔHPIP, P171G, A180E, L118C-A134C, S167A) and then genetically fused it with human albumin (HSA-mFGF21)viaa polypeptide linker. Physicochemical analyses suggested that HSA-mFGF21 was formed from both intact HSA and mFGF21. Pharmacokinetic findings indicated the half-life of HSA-mFGF21 was 20 times longer than that of FGF21. In addition, HSA-mFGF21 was persistently distributed in adipose tissue as a target tissue. Thein vivohypoglycemic activity of HSA-mFGF21 using streptozotocin (STZ)-induced type I diabetes model mice, in which insulin secretion was suppressed, showed that a single intravenous administration of HSA-mFGF21 rapidly alleviated hyperglycemia. At that time, HSA-mFGF21 increased GLUT1 mRNA expression in adipose tissue without having any effect on insulin secretion. A twice weekly administration of HSA-mFGF21 continuously suppressed blood glucose levels and ameliorated the abnormalities of adipose tissue induced by STZ treatment. Interestingly, HSA-mFGF21 showed no hypoglycemic effects in healthy mice. Together, HSA-mFGF21 could be a novel biotherapeutic for the treatment of metabolic disorders including diabetes mellitus.