Paracrine-endocrine FGF chimeras as potent therapeutics for metabolic diseases
Paracrine-endocrine FGF chimeras as potent therapeutics for metabolic diseases
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旁分泌-内分泌 FGF 嵌合体作为代谢疾病的有效治疗方法
DOI：
10.1016/j.ebiom.2019.09.052
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发表时间：
2019
期刊：
影响因子：
11.1
通讯作者：
Zhifeng Huang
中科院分区：
文献类型：
--
作者：
Longwei Zhao;Jianlou Niu;Huan Lin;Jing Zhao;Yang Liu;Zihui Song;Congshang Xiang;Xiaojie Wang;Yong Yang;Xiaokun Li;Moosa Mohammadi;Zhifeng Huang
背景成纤维细胞生长因子21（FGF 21）是一种具有临床应用价值的激素，但其固有的不稳定性和与FGF受体（FGFR）的弱亲和力阻碍了其发展。有一个迫切需要创新的方法来克服这些limitations.MethodsWe设计了一个基于结构的嵌合策略，其中我们取代了热不稳定和低受体亲和力核心的FGF 21与HS结合缺陷的内分泌核心来自一个稳定的和高受体亲和力旁分泌FGF 1（FGF 1 ΔHBS）。采用热位移实验、SPR、SEC-MALS和细胞研究等方法测定了嵌合体的热稳定性、受体结合能力、硫酸乙酰肝素和βKlotho辅受体依赖性。在正常和糖尿病小鼠和猴中分析了半衰期、组织分布、降糖活性和脂肪组织重塑。结果工程嵌合体（FGF 1 Δ HBS-FGF 21 C-tail）的熔解温度相对于野生型FGF 21（FGF 21 WT）增加了1.22 °C，并导致体内半衰期增加了1.55倍。嵌合体还获得了结合FGFR 1c同种型的能力-介导FGF 21代谢作用的主要受体-因此在纠正高血糖症和改善胰岛素抵抗indb/db小鼠中比FGF 21 W显著更有效。我们的嵌合FGF 21也发挥了显着的有益效果，血糖控制在自发性糖尿病食蟹猴。InterpretationOur研究描述了一种基于结构的嵌合方法，有效地减轻了固有的弱受体结合亲和力和短半衰期的内分泌FGF，并推进FGF 21激素的发展成为一个潜在的有用的药物2型糖尿病。
BackgroundThe development of a clinically useful fibroblast growth factor 21 (FGF21) hormone has been impeded by its inherent instability and weak FGF receptor (FGFR) binding affinity. There is an urgent need for innovative approaches to overcome these limitations.MethodsWe devised a structure-based chimerisation strategy in which we substituted the thermally labile and low receptor affinity core of FGF21 with an HS binding deficient endocrinised core derived from a stable and high receptor affinity paracrine FGF1 (FGF1ΔHBS). The thermal stability, receptor binding ability, heparan sulfate and βKlotho coreceptor dependency of the chimera were measured using a thermal shift assay, SPR, SEC-MALS and cell-based studies. The half-life, tissue distribution, glucose lowering activity and adipose tissue remodeling were analyzed in normal and diabetic mice and monkeys.FindingsThe melting temperature of the engineered chimera (FGF1ΔHBS-FGF21C-tail) increased by ∼22 °C relative to wild-type FGF21 (FGF21WT), and resulted in a ∼5-fold increase in half-lifein vivo. The chimera also acquired an ability to bind the FGFR1c isoform – the principal receptor that mediates the metabolic actions of FGF21 – and consequently was dramatically more effective than FGF21WTin correcting hyperglycemia and in ameliorating insulin resistance indb/dbmice. Our chimeric FGF21 also exerted a significant beneficial effect on glycemic control in spontaneous diabetic cynomolgus monkeys.InterpretationOur study describes a structure-based chimerisation approach that effectively mitigates both the intrinsically weak receptor binding affinities and short half-lives of endocrine FGFs, and advance the development of the FGF21 hormone into a potentially useful drug for Type 2 diabetes.