Guo Yiqing, Bao Yuxuan, Chen Zhichao, Rao Zhiheng, Luo Yongde, Ye Sheng, Liu Si
Frontiers Science Center for Synthetic Biology (Ministry of Education), Tianjin Key Laboratory of Function and Application of Biological Macromolecular Structures, School of Life Sciences, Tianjin University, Tianjin 300072, China.
School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China.
Acta Biochim Biophys Sin (Shanghai). 2024 Dec 24;57(4):582-587. doi: 10.3724/abbs.2024227.
Fibroblast growth factor 21 (FGF21) plays a pivotal role in regulating metabolic processes and energy homeostasis, making it a promising therapeutic avenue for various obesity-related conditions. However, its therapeutic efficacy faces challenges due to its suboptimal pharmacokinetics and bioactivity. To overcome these limitations, we adapt a strategy in which key amino acid residues responsible for enhanced activity are pinpointed through sequence alignment and comparative analysis to develop long-acting FGF21 analogs. The mutant FGF21 analogs are fused with the Fc fragment. Here, we report the design, identification, and characterization of two distinct Fc-fused FGF21 analogs, Fc-FGF21(P119R) and Fc-FGF21(H125R), with significantly augmented potency. These findings hold promise for clinical applications, offering potential interventions for obesity-related metabolic disorders.
成纤维细胞生长因子21（FGF21）在调节代谢过程和能量平衡中起着关键作用，使其成为治疗各种肥胖相关病症的有前景的治疗途径。然而，由于其不理想的药代动力学和生物活性，其治疗效果面临挑战。为了克服这些限制，我们采用了一种策略，即通过序列比对和比较分析确定负责增强活性的关键氨基酸残基，以开发长效FGF21类似物。突变型FGF21类似物与Fc片段融合。在此，我们报告了两种不同的Fc融合FGF21类似物Fc-FGF21(P119R)和Fc-FGF21(H125R)的设计、鉴定和表征，它们具有显著增强的效力。这些发现为临床应用带来了希望，为肥胖相关的代谢紊乱提供了潜在的干预措施。
