Obesity is a considerable health concern with limited pharmacotherapy options of low efficacy. Here, we develop a GLP-1/GDF15 fusion protein and explore its weight-lowering potential in animals. The molecule, QL1005, is engineered via fusing GLP-1 and GDF15 analogs by a peptide linker and conjugating it to a fatty acid for time-action extension. In vitro, the potency of QL1005 is superior to the GLP-1 analog semaglutide. In obese mice, QL1005 induces reductions in body weight, food intake, insulin, fasting glucose, and triglycerides. Notably, these metabolic effects come as a result of activities emanating from both GLP-1 and GDF15, in an individual pathway-balanced fashion. In a cynomolgus monkey model of obesity, QL1005 reduces body weight, food intake, insulin, and glucose in a dose-dependent manner with limited incidence of GI side effects. Altogether, this long-acting, dual GLP-1/GDF15 molecule demonstrates the promise of poly-pharmaceutical approaches in metabolic drug discovery and development.

肥胖是一个相当大的健康问题，药物治疗选择有限且疗效低下。在这里，我们开发了一种 GLP-1/GDF15 融合蛋白，并探索了它在动物身上的减肥潜力。该分子 QL1005 是通过肽接头融合 GLP-1 和 GDF15 类似物并将其与脂肪酸结合以延长作用时间而设计的。体外，QL1005 的效力优于 GLP-1 类似物 semaglutide。在肥胖小鼠中，QL1005 诱导体重、食物摄入、胰岛素、空腹血糖和甘油三酯的减少。值得注意的是，这些代谢效应是 GLP-1 和 GDF15 以个体途径平衡方式产生的活动的结果。在食蟹猴肥胖模型中，QL1005 以剂量依赖的方式降低体重、食物摄入、胰岛素和葡萄糖，并且胃肠道副作用的发生率有限。总而言之，这种长效双 GLP-1/GDF15 分子展示了多药物方法在代谢药物发现和开发中的前景。