Glucagon-like peptide-1 receptor (GLP-1R) and glucose-dependent insulinotropic polypeptide receptor (GIPR) co-agonists have emerged as treatment options for reversing diabetes and obesity. Here, we screened the high potency receptor-biased GLP-1R agonists via a newly designed high-throughput GLP-1R extracellular domain (ECD)-based system and demonstrated its in vitro and in vivo therapeutic characters. Twelve 9-mer peptides (named XEL1-XEL12) which were screened from a large phage-displayed peptide library were fused to the N-terminus of GIP (3-30) to generate another twelve fusion peptides, termed XEL13-24. Using the six lysine-altered XEL17 as leading sequences, eighteen fatty chain modified fusion peptides were further assessed via in vitro GLP-1R/GIPR-based cell assay. Moreover, the acute and long-acting in vivo effects of selected candidate on diabetic db/db mice and diet-induced obesity (DIO) rats were both carefully evaluated. XEL17 exhibited balanced activation potency on GLP-1R/GIPR in stable cell lines, and further assessment was performed to evaluate the XEL32, a fatty chain modified XEL17 derivative. Preclinical pharmacodynamic results in diabetic db/db mice demonstrated that XEL32 held outstanding insulinotropic and glucose-lowering activities. In addition, protracted antidiabetic effects of XEL32 were also proved by the hypoglycemic test and multiple oral glucose tolerance test. Furthermore, chronic treatment of XEL32 in DIO rats exhibited outstanding beneficial effects on body weight control, fat loss, food intake control, hemoglobin A1C (HbA1C) reduction as well as the glucose tolerance. XEL32, as a novel GLP-1/GIP dual receptor agonist, may supply efficient glycemic control and weight loss.

中文翻译：

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快速选择一种新型 GLP-1/GIP 双受体激动剂，可延长啮齿动物的血糖控制和体重减轻

胰高血糖素样肽 1 受体 (GLP-1R) 和葡萄糖依赖性促胰岛素多肽受体 (GIPR) 共激动剂已成为逆转糖尿病和肥胖症的治疗选择。在这里，我们通过新设计的高通量 GLP-1R 细胞外结构域 (ECD) 系统筛选了高效受体偏向的 GLP-1R 激动剂，并证明了其体外和体内治疗特性。从大型噬菌体展示肽库中筛选出的 12 条 9 聚体肽（称为 XEL1-XEL12）与 GIP（3-30）的 N 末端融合，生成另外 12 条融合肽，称为 XEL13-24。使用六个赖氨酸改变的 XEL17 作为前导序列，通过体外基于 GLP-1R/GIPR 的细胞测定进一步评估了十八个脂肪链修饰的融合肽。此外，还仔细评估了所选候选药物对糖尿病 db/db 小鼠和饮食诱导肥胖 (DIO) 大鼠的急性和长效体内作用。 XEL17 在稳定细胞系中对 GLP-1R/GIPR 表现出平衡的激活效力，并进行了进一步评估以评估 XEL32（一种脂肪链修饰的 XEL17 衍生物）。糖尿病 db/db 小鼠的临床前药效学结果表明，XEL32 具有出色的促胰岛素和降血糖活性。此外，降血糖试验和多次口服葡萄糖耐量试验也证明了XEL32的长效抗糖尿病作用。此外，XEL32对DIO大鼠的长期治疗对体重控制、脂肪减少、食物摄入控制、血红蛋白A1C (HbA1C)降低以及葡萄糖耐量显示出显着的有益作用。 XEL32作为一种新型GLP-1/GIP双受体激动剂，可以提供有效的血糖控制和减肥作用。