成纤维细胞生长因子21的修饰方法及临床应用价值

Modification Methods and Clinical Application Value of Fibroblast Growth Factor 21

成纤维细胞生长因子21(Fibroblast growth factor 21,FGF21)是机体在应激状态下诱导产生的激素,在调节糖脂代谢及能量稳态方面发挥重要的作用。研究发现,FGF21具有减轻体重、降低血糖、提高胰岛素敏感性、改善血脂异常、改善心血管疾病等生理活性,也是近年来非酒精性脂肪肝炎(Non-alcoholic steatohepatitis,NASH)药物研发中最受关注的靶点之一。但是由于FGF21稳定性差、半衰期短,导致FGF21在临床应用中药效较差,因此定点突变、体外修饰及融合表达等技术被用于FGF21的改造,通过突变酶切位点、引入二硫键、增加分子量等手段达到提高稳定性、延长半衰期、增强药效的目的。本文详细介绍了近年来处于临床及临床前研究中FGF21类似物的修饰、改造方法及临床前和临床研究成果,为FGF21药物的开发提供参考。

Fibroblast growth factor 21(FGF21)is a stress-inducible hormone that plays an important role in regulating glucose and lipid metabolism and energy balance.Administration of FGF21 causes considerable pharmacological benefits,including a reduction in body weight and alleviation of hyperglycaemia,insulin resistance,dyslipidaemia,cardiovascular disorders,and it has been also one of the most concerned targets in the research and development of NASH drugs in recent years.However,due to the poor stability,short half-life and poor efficacy of FGF21,the use of site-directed mutagenesis,fusion expression,in vitro modification and other technical means to modify FGF21 can increase the expression,purification and stability of FGF21 in vivo,extend the half-life,and enhance the efficacy,by mutated enzyme cutting site,introducted disulfide bond,increased molecular weight.This article describes in detail the modification,transformation methods and pharmacodynamic properties of FGF21 analogs in clinical and preclinical studies in recent years,it has provided reference for the development of FGF21 drugs.