PDF(Pubmed)
Abstract：
FGF21 is an endocrine signaling protein belonging to the family of fibroblast growth factors (FGFs). It has emerged as a molecule of interest for treating various metabolic diseases due to its role in regulating glucogenesis and ketogenesis in the liver. However, FGF21 is prone to heat, proteolytic, and acid-mediated degradation, and its low molecular weight makes it susceptible to kidney clearance, significantly reducing its therapeutic potential. Protein engineering studies addressing these challenges have generally shown that increasing the thermostability of FGF21 led to improved pharmacokinetics. Here, we describe the computer-aided design and experimental characterization of FGF21 variants with enhanced melting temperature up to 15 °C, uncompromised efficacy at activation of MAPK/ERK signaling in Hep G2 cell culture, and ability to stimulate proliferation of Hep G2 and NIH 3T3 fibroblasts cells comparable with FGF21-WT. We propose that stabilizing the FGF21 molecule by rational design should be combined with other reported stabilization strategies to maximize the pharmaceutical potential of FGF21.
摘要：
FGF21是属于成纤维细胞生长因子(FGF)家族的内分泌信号蛋白。由于其在调节肝脏中的葡萄糖生成和酮生成中的作用，它已成为治疗各种代谢疾病的感兴趣分子。然而,FGF21容易发热,蛋白水解，和酸介导的降解，它的低分子量使它容易被肾脏清除，显著降低其治疗潜力。解决这些挑战的蛋白质工程研究通常表明，增加FGF21的热稳定性导致改善的药代动力学。这里,我们描述了FGF21变体的计算机辅助设计和实验表征，其熔融温度高达15°C，在HepG2细胞培养中激活MAPK/ERK信号传导的不妥协功效，和刺激HepG2和NIH3T3成纤维细胞增殖的能力与FGF21-WT相当。我们建议通过合理设计稳定FGF21分子应与其他报道的稳定策略相结合，以最大化FGF21的药物潜力。
