GRK-biased adrenergic agonists for the treatment of type 2 diabetes and obesity

Biased agonism of G protein-coupled receptors (GPCRs) offers potential for safer medications. Current efforts have explored the balance between G proteins and β-arrestin; however, other transducers like GPCR kinases (GRKs) remain understudied. GRK2 is essential for β2 adrenergic receptor (β2AR)-mediated glucose uptake, but β2AR agonists are considered poor clinical candidates for glycemic management due to Gs/cAMP-induced cardiac side effects and β-arrestin-dependent desensitization. Using ligand-based virtual screening and chemical evolution, we developed pathway-selective agonists of β2AR that prefer GRK coupling. These compounds perform well in preclinical models of hyperglycemia and obesity and demonstrate a lower potential for cardiac and muscular side effects compared to standard β2-receptor agonists and incretin mimetics respectively. Furthermore, the lead candidate showed favorable pharmacokinetics and was well-tolerated in a placebo-controlled clinical trial. GRK-biased β2AR partial agonists are thus promising oral alternatives to injectable incretin mimetics used in the treatment of type 2 diabetes and obesity.

G蛋白偶联受体（G protein-coupled receptors, GPCRs）的偏向性激动为开发更安全的药物提供了潜在可能。当前研究已围绕G蛋白与β抑制蛋白之间的调控平衡展开探索，但诸如G蛋白偶联受体激酶（GPCR kinases, GRKs）这类其他转导蛋白的相关研究仍相对不足。G蛋白偶联受体激酶2（GRK2）是β2肾上腺素能受体（β2 adrenergic receptor, β2AR）介导葡萄糖摄取过程中的关键调控因子，但由于Gs蛋白/环磷酸腺苷（Gs/cAMP）通路激活会诱发心脏副作用，且存在β抑制蛋白依赖的受体脱敏效应，β2AR激动剂被认为并非血糖管理的优质临床候选药物。本研究通过基于配体的虚拟筛选与化学进化技术，开发出了偏好与GRK结合的β2AR通路选择性激动剂。相较于经典β2受体激动剂与肠促胰岛素模拟剂，此类化合物在高血糖症与肥胖的临床前模型中表现出色，且分别展现出更低的心脏与肌肉副作用风险。此外，该先导化合物具备良好的药代动力学特性，并在一项安慰剂对照临床试验中表现出良好的耐受性。因此，GRK偏向性β2AR部分激动剂有望成为用于治疗2型糖尿病与肥胖的注射用肠促胰岛素模拟剂的口服替代方案。