Zhou Yan, Li Jianhui, Gao Guosheng, Li Yafeng, Zhang Changzhen
Department of Pharmacy, Ningbo No. 2 Hospital, Ningbo, China.
Department of Endocrinology, Ningbo No. 2 Hospital, Ningbo, China.
Heliyon. 2024 Jan 11;10(2):e24340. doi: 10.1016/j.heliyon.2024.e24340. eCollection 2024 Jan 30.
In recent years, glucagon-like peptide-1 (GLP-1) has demonstrated considerable potential in the treatment of type 2 diabetes (T2D) and obesity. However, the half-life of naturally occurring GLP-1 is quite short . Two common strategies employed for half-life extension are the use of the Albumin-binding domain (ABD) and XTEN polypeptide, which operate through different mechanisms. In this study, we designed an innovative GLP-1 receptor agonist with an extended duration of action. This new construct incorporated an albumin binding domain (ABD) and an XTEN sequence (either XTEN144 or XTEN288) as carriers. We referred to these fusion proteins as GLP-ABD-XTEN144 and GLP-ABD-XTEN288. In an system, the said constructs were efficaciously produced in substantial quantity. It was observed from studies that the fusion protein GLP-ABD-XTEN144 demonstrated a five times stronger affinity towards human serum albumin (HSA), boasting a binding affinity () of 5.50 nM. This was in contrast to GLP-ABD-XTEN288, whose value was registered at 27.78 nM. Moreover, GLP-ABD-XTEN144 presented a half-life of 12.9 h in mice, thus exceeding the corresponding value for GLP-ABD-XTEN288, 7.32 h in mice. Both these fusion proteins significantly mitigated non-fasting blood sugar levels and overall food consumption for 48 h subsequent to a one-time injection in mice. Notably, GLP-ABD-XTEN144 exhibited more pronounced hypoglycemic activity and food inhibitory effects than GLP-ABD-XTEN288. The designed GLP-ABD-XTEN144 fusion protein shows promising prospects for clinical application in T2D treatment. Our findings also suggest that ABD and XTEN polypeptides synergistically contribute to half-life extension, further enhancing the pharmacokinetic characteristics of a payload.
近年来，胰高血糖素样肽-1（GLP-1）在2型糖尿病（T2D）和肥胖症治疗中展现出了巨大潜力。然而，天然存在的GLP-1半衰期相当短。延长半衰期常用的两种策略是使用白蛋白结合域（ABD）和XTEN多肽，它们通过不同机制发挥作用。在本研究中，我们设计了一种作用持续时间延长的创新型GLP-1受体激动剂。这种新构建体纳入了白蛋白结合域（ABD）和XTEN序列（XTEN144或XTEN288）作为载体。我们将这些融合蛋白称为GLP-ABD-XTEN144和GLP-ABD-XTEN288。在一个系统中，上述构建体能够大量有效产生。从研究中观察到，融合蛋白GLP-ABD-XTEN144对人血清白蛋白（HSA）的亲和力强五倍，其结合亲和力（）为5.50 nM。相比之下，GLP-ABD-XTEN288的该值为27.78 nM。此外，GLP-ABD-XTEN144在小鼠体内的半衰期为12.9小时，超过了GLP-ABD-XTEN288在小鼠体内的相应值7.32小时。在小鼠单次注射后48小时内，这两种融合蛋白均显著降低了非空腹血糖水平并减少了总体食物摄入量。值得注意的是，GLP-ABD-XTEN144比GLP-ABD-XTEN288表现出更显著的降血糖活性和食物抑制作用。所设计的GLP-ABD-XTEN144融合蛋白在T2D治疗的临床应用中显示出了广阔前景。我们的研究结果还表明，ABD和XTEN多肽协同作用有助于延长半衰期，进一步增强了有效载荷的药代动力学特性。
