Sloop Kyle W, Cox Amy L, Wainscott David B, White Alex, Droz Brian A, Stutsman Cynthia, Showalter Aaron D, Suter Todd M, Dunbar James D, Snider Brandy M, O'Farrell Libbey S, Hewitt Natalie, Ruble J Craig, Padgett Leah R, Woerly Eric M, Peterson Jeffrey A, Coskun Tamer, Liu Zhaomin, Coutant David E, Ai Minrong, Emmerson Paul J, Sangwung Panjamaporn, Willard Francis S
Diabetes, Obesity and Complications, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA.
Molecular Pharmacology, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indianapolis, IN 46285, USA.
Sci Transl Med. 2024 Dec 18;16(778):eadp5765. doi: 10.1126/scitranslmed.adp5765.
Orally bioavailable, synthetic nonpeptide agonists (NPAs) of the glucagon-like peptide-1 receptor (GLP-1R) may offer an effective, scalable pharmacotherapy to address the metabolic disease epidemic. One of the first molecules in the emerging class of GLP-1R NPAs is orforglipron, which is in clinical development for treating type 2 diabetes and obesity. Here, we characterized the pharmacological properties of orforglipron in comparison with peptide-based GLP-1R agonists and other NPAs. Competition binding experiments using either [I]GLP-1(7-36)NH or [H]orforglipron indicated that orforglipron is a high-affinity [inhibition constant () = 1 nM], selective ligand of the human GLP-1R. Signal transduction assays showed that orforglipron has low intrinsic efficacy for effector activation and negligible β-arrestin recruitment. To evaluate GLP-1R engagement in vivo, mice expressing the human GLP-1R were administered orforglipron and subjected to a glucose tolerance test. Predicted receptor occupancy was calculated using the receptor value of orforglipron and its unbound concentration in vivo that reduces hyperglycemia. These experiments revealed that low GLP-1R occupancy by orforglipron is sufficient to yield a full biological response. Moreover, in a model where CRISPR-Cas9 gene editing was used to sensitize the rat GLP-1R () to GLP-1R NPAs, target engagement by orforglipron in the pancreas and brain was consistent with peptide-based GLP-1R agonists. Diet-induced obesity in rats enabled studies showing weight loss in animals orally administered orforglipron versus subcutaneous injection of GLP-1R agonist semaglutide. Furthermore, crossover studies indicated oral orforglipron can sustain efficacy initiated by parenteral semaglutide. The pharmacological properties of orforglipron may inform targeting of other peptide receptors with NPAs.
胰高血糖素样肽-1受体（GLP-1R）的口服生物可利用合成非肽激动剂（NPAs）可能提供一种有效、可扩展的药物疗法来应对代谢疾病的流行。在新兴的GLP-1R NPAs类别中，最早的分子之一是奥佛利肽，它正处于治疗2型糖尿病和肥胖症的临床开发阶段。在此，我们将奥佛利肽的药理学特性与基于肽的GLP-1R激动剂和其他NPAs进行了比较。使用[I]GLP-1(7-36)NH或[H]奥佛利肽进行的竞争结合实验表明，奥佛利肽是一种高亲和力[抑制常数（）=1 nM]的人GLP-1R选择性配体。信号转导分析表明，奥佛利肽对效应器激活的内在效力较低，且β-抑制蛋白募集可忽略不计。为了评估体内GLP-1R的参与情况，给表达人GLP-1R的小鼠施用奥佛利肽，并进行葡萄糖耐量试验。使用奥佛利肽的受体值及其体内降低高血糖的未结合浓度计算预测的受体占有率。这些实验表明，奥佛利肽的低GLP-1R占有率足以产生完全的生物学反应。此外，在一个使用CRISPR-Cas9基因编辑使大鼠GLP-1R（）对GLP-1R NPAs敏感的模型中，奥佛利肽在胰腺和大脑中的靶点参与情况与基于肽的GLP-1R激动剂一致。大鼠的饮食诱导肥胖使得研究表明，口服奥佛利肽的动物与皮下注射GLP-1R激动剂司美格鲁肽相比体重减轻。此外，交叉研究表明口服奥佛利肽可以维持由肠胃外司美格鲁肽启动的疗效。奥佛利肽的药理学特性可能为用NPAs靶向其他肽受体提供参考。
