Glucagon

近日，上海交通大学医学院附属瑞金医院医药结构生物学转化研究中心周庆同副研究员和王明伟教授等受邀在Cell Press期刊Trends in Pharmacological Sciences（TiPS）在线发表了题为“Structural pharmacology and mechanisms of GLP-1R signaling”的长篇综述（封面文章），系统总结了GLP-1R结构药理学与信号转导机制的研究进展，揭示了其信号调控的多样性、精密性和复杂性，为新一代2型糖尿病与肥胖症治疗药物的研发奠定了理论基础。图1. 论文首页标题图2. TiPS封面胰高血糖素样肽-1受体（Glucagon-like peptide-1 receptor, GLP-1R）属于B1类G蛋白偶联受体，在血糖稳态调控中发挥关键作用，是肥胖症和2型糖尿病的治疗靶标1-4。GLP-1R由构象灵活的胞外域（Extracellular domain, ECD）和嵌在细胞膜上的跨膜域（Transmembrane domain, TMD）组成，两者共同参与内源性配体GLP-1的识别和跨膜信号转导。目前共有8款GLP-1R激动剂获批上市，其中7个为GLP-1R单靶点激动剂，尤以司美格鲁肽（Semaglutide）的市场表现为著；另外一个是替尔泊肽（Tirzepatide），为GLP-1R和葡萄糖依赖性促胰岛素释放多肽受体（Glucose-dependent insulinotropic polypeptide receptor, GIPR）双重激动剂2。这些获批药物在减重和降糖方面表现突出，但也存在多种副作用，最常见的是胃肠道反应（如恶心、呕吐和便秘）5，同时用药依从性和停药体重反弹问题亟待解决6。该综述系统回顾了GLP-1R激动剂作为降糖和减重药物的开发历程，详细列举了其三维结构解析的代表性成果，依次从内源性GLP-1的生理功能、GLP-1R激活机制、多肽与小分子激动剂迥异的受体识别模式和变构调节机理等方面揭示了GLP-1R信号调控的多样性、精密性与复杂性。该综述还展望了未来研究的重点，包括不同效应蛋白的识别特征、偏向性信号通路调节、停药体重反弹机制及个体化治疗策略等，指出对GLP-1R结构药理学与信号转导机制的深入理解有助于开发新一代单靶点和多重激动剂。处在非活化状态的GLP-1R，其ECD闭合并与TMD互锁；GLP-1结合后ECD竖直平行与GLP-1的羧基部分紧密互作，而GLP-1的氨基部分则插入TMD的正构位点，引起受体第六跨膜螺旋（Transmembrane helix 6, TM6）胞内侧向外移动，形成G蛋白结合口袋。G蛋白的偶联进一步推动TM6外移，破坏保守极性网络，增强GLP-1R与G蛋白之结合进而加速跨膜信号转导（图3）。图3. 处于不同活性状态下的GLP-1R结构特征。尽管多肽激动剂与GLP-1的序列差异显著，但具有相似的多肽—受体结合界面，特别是ECD和第一胞外环（Extracellular loop 1, ECL1）之构象高度一致（图4）。相比之下，GLP-1的代谢产物GLP-1(9-36)具有独特的结合位点和受体识别模式，与其弱激动活性相符。小分子激动剂则能诱导GLP-1R的ECD以不同方式弯曲靠近TMD，从而形成紧密的结合口袋以增大受体—配体互作面积。此外，正向变构调节剂通过稳定活性构象增强GLP-1(9–36)的弱效信号，而变构激动剂Compound 2则通过诱导ECD氨基端螺旋下移实现受体活化，为靶向GLP-1R的药物设计提供了新的思路（图5）。图4. 内源性GLP-1、多肽类激动剂与小分子激动剂识别和激活GLP-1R的结构特征。图5. GLP-1R的小分子变构调控剂的结合位点。GLP-1R结构药理学与信号转导机制研究已经取得了较多的进展，GLP-1R与Gs蛋白的偶联方式也获阐明，但和其他下游效应蛋白如Gq、Gi、GRK、β-arrestin等的分子互作仍待揭示。偏向激动剂（如ExP5）选择性激活Gs通路，展现出更优的降糖效果，但亦需优化以达到更强的治疗收益。动态结构研究技术（如时间分辨冷冻电镜、分子动力学模拟）将助力捕获受体激活过程中间态和解析变构信号转导网络，而原位断层成像有望揭示生理环境下GLP-1R复合物的结构。在临床层面，除了解决用药依从性和停药体重反弹问题外，通过结构药理学研究结合患者数据挖掘开发个性化疗法将克服因GLP-1R基因多态性导致的个体疗效差异。据悉，王明伟教授领导的团队长期从事GLP-1R激动剂的结构和功能研究，产生了一大批原创性成果，包括发现首个具有体内实验疗效的小分子GLP-1R激动剂（Boc5）7、解析胰高血糖素受体（Glucagon receptor, GCGR）跨膜区8和全长9、GLP-1R（跨膜区）10、GIPR（全长）11以及7个多重激动剂与GLP-1R、GIPR和/或GCGR形成的16个复合物2的三维结构等。上海交通大学医学院附属瑞金医院医药结构生物学转化研究中心课题组组长周庆同副研究员为该文的第一作者，王明伟教授为通讯作者。参与该文撰写的还有中国科学院上海药物研究所赵丰辉副研究员、杨德华研究员以及复旦大学基础医学院药理学系博士研究生张耀。文章链接： https://doi.org/10.1016/j.tips.2025.03.003参考文献1. Graaf, C.; Donnelly, D.; Wootten, D.; Lau, J.; Sexton, P.M.; Miller, L.J.; Ahn, J.M.; Liao, J.; Fletcher, M.M.; Yang, D.; et al. Glucagon-like peptide-1 and its class B G protein-coupled receptors: a long march to therapeutic successes. Pharmacol Rev 2016, 68 (4), 954-1013.2. Zhou, Q.; Li, G.; Hang, K.; Li, J.; Yang, D.; Wang, M. W. Weight loss blockbuster development: a role for unimolecular polypharmacology. Annu Rev Pharmacol Toxicol 2025, 65 (1), 191-213.3. Drucker, D.J. GLP-1 physiology informs the pharmacotherapy of obesity. Mol Metab 2022, 57, 101351.4. Wen, X.; Zhang, B.; Wu, B.; Xiao, H.; Li, Z.; Li, R.; Xu, X.; Li, T. Signaling pathways in obesity: mechanisms and therapeutic interventions. Signal Transduct Target Ther 2022, 7 (1), 298.5. Gorgojo-Martínez, J.J.; Mezquita-Raya, P.; Carretero-Gómez, J.; Castro, A.; Cebrián-Cuenca, A.; de Torres-Sánchez, A.; García-de-Lucas, M.D.; Núñez, J.; Obaya, J. C.; Soler, M.J.; et al. Clinical recommendations to manage gastrointestinal adverse events in patients treated with GLP-1 receptor agonists: a multidisciplinary expert consensus. J Clin Med 2023, 12 (1), 145.6. Wilding, J.P.H.; Batterham, R.L.; Davies, M.; Van Gaal, L.F.; Kandler, K.; Konakli, K.; Lingvay, I.; McGowan, B. M.; Oral, T.K.; Rosenstock, J.; et al. Weight regain and cardiometabolic effects after withdrawal of semaglutide: the STEP 1 trial extension. Diabetes Obes Metab 2022, 24 (8), 1553-1564.7. Chen, D.; Liao, J.; Li, N.; Zhou, C.; Liu, Q.; Wang, G.; Zhang, R.; Zhang, S.; Lin, L.; Chen, K.; et al. A nonpeptidic agonist of glucagon-like peptide 1 receptors with efficacy in diabetic db/db mice. Proc Natl Acad Sci U S A 2007, 104 (3), 943-948.8. Siu, F.Y.; He, M.; de Graaf, C.; Han, G.W.; Yang, D.; Zhang, Z.; Zhou, C.; Xu, Q.; Wacker, D.; Joseph, J.S.; et al. Structure of the human glucagon class B G-protein-coupled receptor. Nature 2013, 499 (7459), 444-449.9. Zhang, H.; Qiao, A.; Yang, D.; Yang, L.; Dai, A.; de Graaf, C.; Reedtz-Runge, S.; Dharmarajan, V.; Zhang, H.; Han, G.W.; et al. Structure of the full-length glucagon class B G-protein-coupled receptor. Nature 2017, 546 (7657), 259-264.10. Song, G.; Yang, D.; Wang, Y.; de Graaf, C.; Zhou, Q.; Jiang, S.; Liu, K.; Cai, X.; Dai, A.; Lin, G.; et al. Human GLP-1 receptor transmembrane domain structure in complex with allosteric modulators. Nature 2017, 546 (7657), 312-315.11. Zhao, F.; Zhang, C.; Zhou, Q.; Hang, K.; Zou, X.; Chen, Y.; Wu, F.; Rao, Q.; Dai, A.; Yin, W. Structural insights into hormone recognition by the human glucose-dependent insulinotropic polypeptide receptor. Elife 2021, 10, e68719识别微信二维码，可添加药时空小编请注明：姓名+研究方向！

The Phase 3 trial results of Boan Biotech’s BA5101 (Dulagutide Injection, formerly code-named LY05008) were recently published in Journal of Diabetes.BA5101 is a biosimilar to Trulicity® indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. The Biologics License Application (BLA) of BA5101 is under review in China currently. It is the world’s first and only biosimilar to Trulicity to submit the BLA.Link: https://onlinelibrary.wiley.com/doi/10.1111/1753-0407.70077Dulaglutide is a long-acting, once-weekly glucagon-like peptide-1 (GLP-1) receptor agonist. Compared with other glucose-lowering medications, dulaglutide can improve β-cell function and achieve stable and effective reductions in blood glucose and HbA1c levels. In addition, due to its unique mechanism of action, the drug is less likely to cause hypoglycemia and can reduce body weight, blood lipids, and the risk of long-term cardiovascular complications. It also demonstrates kidney benifits1. Multiple clinical studies have also shown that its weekly administration helps to reduce the patient inconvenience and its gastrointestinal adverse reactions are relatively mild, both of which contribute to better patient compliance.The development of BA5101 strictly followed relevant guidelines for biosimilars in China, the U.S., and the EU. The drug’s overall similarity to the reference product, Trulicity, has been established by evidence from a series of analytical, non-clinical, comparative human pharmacokinetics, and comparative clinical studies. BA5101 has been shown to be highly similar to the reference product in terms of quality, efficacy, safety, and immunogenicity.The Phase 3 study of BA5101, led by Professor Guo Lixing from Beijing Hospital, is a multi-center, randomized, open-label, active comparator study designed to compare the efficacy and safety between BA5101 and Trulicity in treating Chinese adults with type 2 diabetes mellitus. In this study, 440 patients were randomly assigned 1:1 to receive a subcutaneous injection of 1.5 mg BA5101 (n=222) or Trulicity(n=218) once weekly for 24 weeks.The primary endpoint was the mean change in HbA1c from baseline to Week 24. The secondary endpoints included the mean change in HbA1c from baseline to Week 12; the proportion of patients who had achieved HbA1c ≤ 6.5% at Weeks 12 and 24; and the mean change in body weight, fasting plasma glucose (FPG) level, and 2-h postprandial plasma glucose (PPG) level from baseline to Weeks 12 and 24. Safety, PK, and immunogenicity profiles were also included for data analysis. All the endpoints in the study were met. BA5101 was shown to rapidly, stably and sustainably lower blood glucose level as well as reduce body weight. Overall, it demonstrated equivalent efficacy to Trulicity in Chinese patients with type 2 diabetes mellitus as well as comparable safety, immunogenicity, and PK profiles against Trulicity.The global diabetic population is huge. According to the latest data from the International Diabetes Federation (IDF), 589 million adults aged 20 to 79 were living with diabetes worldwide in 2024, a number projected to rise to 853 million by 2050. China has the largest diabetic population of any country, with 148 million adults affected in 2024 -- accounting for 25% of the global total. This figure is expected to grow to 168 million by 2025.2 Amid such significant unmet medical needs, the market outlook for long-acting GLP-1 receptor agonists is increasingly promising. Publicly available data show that the global sales of Trulicity reached approximately USD 5.25 billion in 2024.3Dr. Changlin Dou, President of R&D and Chief Operating Officer at Boan Biotech, said: “The nature of dulaglutide as a peptide-Fc fusion protein presents formidable CMC challenges in any biosimilar development. Through a rigorous clinical program, the overall similarity between BA5101 and Trulicity has been demonstrated. BA5101’s Phase 1 results were published in Expert Opinion on Biological Therapy in 2023.4 The publication of these two articles reflects the recognition by international scientific community of the quality and data of the clinical studies of BA5101. We are ahead of the global competition with respect to the development of BA5101 as it is the first dulaglutide biosimilar allowed to proceed to clinical study in the U.S.. We look forward to its ex-China development and launch so that we can offer diabetic patients around the world an affordable, high-quality treatment option.” About Boan BiotechBoan Biotech (6955.HK) is a fully-integrated biopharmaceutical company developing, manufacturing, and marketing biologics, with a focus on oncology, autoimmune diseases, ophthalmology, and metabolic diseases. The company's drug discovery activities revolve around multiple platforms: Human Antibody Transgenic Mouse and Phage Display Technology Platform, Bispecific T-cell Engager Technology Platform, ADC Technology Platform and Cell Therapy Platform.Boan Biotech operates across the entire value chain of the industry covering antibody discovery, cell line development, upstream and downstream process development, analytical and bio-analytical method development, technology transfer, non-clinical research, clinical research, regulatory affairs and registration, and commercial production. In the cell therapy field, Boan Biotech focuses on a new generation of enhanced and regulated CAR-T technology, developing safer, more effective, and affordable treatments for patients.Boan Biotech’s portfolio includes three products approved for marketing. Its pipeline includes two investigational drugs under review for their marketing applications, multiple novel biologics as drug candidates protected for their international intellectual property rights, and a number of biosimilar candidates. In addition to China, the company is also developing biopharmaceutical products in overseas markets, including the U.S., the EU, and Japan. With a differentiated portfolio and well-established commercial capabilities, Boan Biotech operates across the industry’s value chain from research and development to manufacturing and commercialization, laying a solid foundation for long-term, high-quality growth in the future.References:1.Hertel C Cerstein, Helen M Colhoun, Gilles R Dagenais, et al. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial [J]. Lancet. https://doi.org/10.1016/S0140-6736(19)31149-32.International Diabetes Federation. https://diabetesatlas.org/.Accessed in April 20253.Eli Lilly and Company 2023 Annual Report. https://investor.lilly.com/static-files/ff06ed54-9f64-4b7f-8529-c0278d635eac. Accessed in April 20254.Qin Zhang, Cheng Sun, Jinying Wu, et al. Pharmacokinetic similarity study comparing the biosimilar candidate, LY05008, with its reference product dulaglutide in healthy Chinese male subjects [J]. Expert Opinion on Biological Therapy. https://doi.org/10.1080/14712598.2023.2189009