胰高血糖素样肽-1及其B类G蛋白偶联受体：通往治疗成功的漫长征程。
Glucagon-Like Peptide-1 and Its Class B G Protein-Coupled Receptors: A Long March to Therapeutic Successes.
作者信息
Graaf Chris de, Donnelly Dan, Wootten Denise, Lau Jesper, Sexton Patrick M, Miller Laurence J, Ahn Jung-Mo, Liao Jiayu, Fletcher Madeleine M, Yang Dehua, Brown Alastair J H, Zhou Caihong, Deng Jiejie, Wang Ming-Wei
机构信息
Division of Medicinal Chemistry, Faculty of Sciences, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands (C.d.G.); School of Biomedical Sciences, University of Leeds, Leeds, United Kingdom (D.D.); Drug Discovery Biology Theme and Department of Pharmacology, Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, Australia (D.W., P.M.S., M.M.F.); Protein and Peptide Chemistry, Global Research, Novo Nordisk A/S, Måløv, Denmark (J.La.); Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Scottsdale, Arizona (L.J.M.); Department of Chemistry and Biochemistry, University of Texas at Dallas, Richardson, Texas (J.-M.A.); Department of Bioengineering, Bourns College of Engineering, University of California at Riverside, Riverside, California (J.Li.); National Center for Drug Screening and CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China (D.Y., C.Z., J.D., M.-W.W.); Heptares Therapeutics, BioPark, Welwyn Garden City, United Kingdom (A.J.H.B.); and School of Pharmacy, Fudan University, Zhangjiang High-Tech Park, Shanghai, China (M.-W.W.).
Division of Medicinal Chemistry, Faculty of Sciences, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands (C.d.G.); School of Biomedical Sciences, University of Leeds, Leeds, United Kingdom (D.D.); Drug Discovery Biology Theme and Department of Pharmacology, Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, Australia (D.W., P.M.S., M.M.F.); Protein and Peptide Chemistry, Global Research, Novo Nordisk A/S, Måløv, Denmark (J.La.); Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Scottsdale, Arizona (L.J.M.); Department of Chemistry and Biochemistry, University of Texas at Dallas, Richardson, Texas (J.-M.A.); Department of Bioengineering, Bourns College of Engineering, University of California at Riverside, Riverside, California (J.Li.); National Center for Drug Screening and CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China (D.Y., C.Z., J.D., M.-W.W.); Heptares Therapeutics, BioPark, Welwyn Garden City, United Kingdom (A.J.H.B.); and School of Pharmacy, Fudan University, Zhangjiang High-Tech Park, Shanghai, China (M.-W.W.)
出版信息
Pharmacol Rev. 2016 Oct;68(4):954-1013. doi: 10.1124/pr.115.011395.
The glucagon-like peptide (GLP)-1 receptor (GLP-1R) is a class B G protein-coupled receptor (GPCR) that mediates the action of GLP-1, a peptide hormone secreted from three major tissues in humans, enteroendocrine L cells in the distal intestine, α cells in the pancreas, and the central nervous system, which exerts important actions useful in the management of type 2 diabetes mellitus and obesity, including glucose homeostasis and regulation of gastric motility and food intake. Peptidic analogs of GLP-1 have been successfully developed with enhanced bioavailability and pharmacological activity. Physiologic and biochemical studies with truncated, chimeric, and mutated peptides and GLP-1R variants, together with ligand-bound crystal structures of the extracellular domain and the first three-dimensional structures of the 7-helical transmembrane domain of class B GPCRs, have provided the basis for a two-domain-binding mechanism of GLP-1 with its cognate receptor. Although efforts in discovering therapeutically viable nonpeptidic GLP-1R agonists have been hampered, small-molecule modulators offer complementary chemical tools to peptide analogs to investigate ligand-directed biased cellular signaling of GLP-1R. The integrated pharmacological and structural information of different GLP-1 analogs and homologous receptors give new insights into the molecular determinants of GLP-1R ligand selectivity and functional activity, thereby providing novel opportunities in the design and development of more efficacious agents to treat metabolic disorders.
胰高血糖素样肽（GLP）-1受体（GLP-1R）是B类G蛋白偶联受体（GPCR），介导GLP-1的作用。GLP-1是一种肽类激素，由人体的三个主要组织分泌，即远端肠道的肠内分泌L细胞、胰腺的α细胞和中枢神经系统。GLP-1发挥着对2型糖尿病和肥胖管理有用的重要作用，包括葡萄糖稳态以及胃动力和食物摄入的调节。已成功开发出具有更高生物利用度和药理活性的GLP-1肽类似物。对截短、嵌合和突变肽以及GLP-1R变体进行的生理和生化研究，连同细胞外结构域的配体结合晶体结构以及B类GPCRs 7螺旋跨膜结构域的首个三维结构，为GLP-1与其同源受体的双结构域结合机制提供了基础。尽管发现具有治疗可行性的非肽类GLP-1R激动剂的努力受到阻碍，但小分子调节剂为肽类似物提供了互补的化学工具，用于研究GLP-1R的配体导向偏向性细胞信号传导。不同GLP-1类似物和同源受体的综合药理学和结构信息为GLP-1R配体选择性和功能活性的分子决定因素提供了新见解，从而为设计和开发更有效的治疗代谢紊乱药物提供了新机会。
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