The N-methyl-d-aspartate (NMDA) receptor is a glutamate-activated cation channel that is critical to many processes in the brain. Genome-wide association studies suggest that glutamatergic neurotransmission and NMDA receptor-mediated synaptic plasticity are important for body weight homeostasis¹. Here we report the engineering and preclinical development of a bimodal molecule that integrates NMDA receptor antagonism with glucagon-like peptide-1 (GLP-1) receptor agonism to effectively reverse obesity, hyperglycaemia and dyslipidaemia in rodent models of metabolic disease. GLP-1-directed delivery of the NMDA receptor antagonist MK-801 affects neuroplasticity in the hypothalamus and brainstem. Importantly, targeting of MK-801 to GLP-1 receptor-expressing brain regions circumvents adverse physiological and behavioural effects associated with MK-801 monotherapy. In summary, our approach demonstrates the feasibility of using peptide-mediated targeting to achieve cell-specific ionotropic receptor modulation and highlights the therapeutic potential of unimolecular mixed GLP-1 receptor agonism and NMDA receptor antagonism for safe and effective obesity treatment.

N-甲基-d-天冬氨酸(NMDA)受体是一种谷氨酸激活的阳离子通道，对大脑中的许多过程至关重要。全基因组关联研究表明，谷氨酸能神经传递和 NMDA 受体介导的突触可塑性对于体重稳态很重要¹。在这里，我们报告了一种双峰分子的工程和临床前开发，该分子将 NMDA 受体拮抗作用与胰高血糖素样肽 1 (GLP-1) 受体激动作用相结合，以有效逆转代谢疾病啮齿动物模型中的肥胖、高血糖和血脂异常。 GLP-1 定向递送 NMDA 受体拮抗剂 MK-801 影响下丘脑和脑干的神经可塑性。重要的是，MK-801 靶向表达 GLP-1 受体的大脑区域可以避免与 MK-801 单一疗法相关的不良生理和行为影响。总之，我们的方法证明了使用肽介导的靶向来实现细胞特异性离子型受体调节的可行性，并强调了单分子混合 GLP-1 受体激动剂和 NMDA 受体拮抗剂在安全有效的肥胖治疗中的治疗潜力。