Dynamic folding modulation generates FGF21 variant against diabetes

Fibroblast growth factor 21 (FGF21) is a regulator of glucose and lipid metabolism. It has been widely considered as a promising candidate for the treatment of type 2 diabetes mellitus (T2DM) and other related metabolic disorders. However, lack of structural and dynamic information has limited FGF21-based drug development. Here, using nuclear magnetic resonance (NMR) spectroscopy, we determine the structure of FGF21 and find that its non-canonical flexible b-trefoil conformation affects the folding of b2-b3 hairpin and further overall protein stability. To modulate folding dynamics, we designed an FGF21-FGF19 chimera, FGF21SS. As expected, FGF21SS shows better thermostability without inducing hepatocyte proliferation. Functional characterization of FGF21SS shows its better insulin sensitivity, reduced inflammation in 3T3-L1 adipocytes, and lower blood glucose and insulin levels inob/ob mice compared with wild type. Our dynamics-based rational design provides a promising approach for FGF21-based therapeutic development against T2DM.

成纤维细胞生长因子21（FGF21）是葡萄糖与脂质代谢的调节因子。它被广泛认为是治疗2型糖尿病（T2DM）及其他相关代谢紊乱的潜在候选药物。然而，结构与动态信息的缺失限制了基于FGF21的药物研发。在此，我们利用核磁共振（nuclear magnetic resonance, NMR）波谱技术解析了FGF21的结构，发现其非经典柔性β-三叶形构象会影响β2-β3发夹的折叠，进而影响蛋白质的整体稳定性。为调控折叠动力学，我们设计了一种FGF21-FGF19嵌合体FGF21SS。正如预期，FGF21SS表现出更优的热稳定性，且不会诱导肝细胞增殖。对FGF21SS的功能表征显示，与野生型相比，它具有更优的胰岛素敏感性，能减轻3T3-L1脂肪细胞的炎症反应，并降低ob/ob小鼠的血糖与胰岛素水平。我们基于动力学的理性设计为针对T2DM的FGF21疗法研发提供了一种潜在策略。