余刚;王永祥;

• 1:上海交通大学药学院分子与系统药理学研究室

摘要(Abstract)：

近年来,胰高血糖素样肽.1(GLP-1)受体激动剂成为2型糖尿病治疗的新型药物。天然结构GLP-1受体激动剂受到体内二肽基肽酶(DPP-Ⅳ)和中性内肽酶(NEP)的酶切作用而易迅速降解。长效GLP-1受体激动剂通过对天然结构多肽作氨基酸点突变和加大分子量的结构修饰,可以有效抑制药物在循环系统和泌尿系统的酶降解,延长药物作用时间。本文通过分析GLP-1受体激动剂的酶降解过程及介绍现有临床药物的研究进展,以促进该类药物的研究开发。

关键词(KeyWords)： 胰高血糖素样肽-1;胰高血糖素样肽-1受体激动剂;EXENDIN-4;二肽基肽酶;中性内肽酶

Abstract:

Keywords:

基金项目(Foundation):

作者(Authors): 余刚;王永祥;

DOI: 10.19577/j.cnki.issn10074406.2013.04.017

参考文献(References)：

• [1]Perfetti R,Merkel P.Glueagon-like peptide-1:a major regulator of pancreaticβ-cell function function[J].Ear J Endoerinol,2000,143(6):717.
• [2]Wang B,Zhaong J,Lin H,et al.Blood pressure-lowering effects of GLP-1 receptor agonists exenatide and liraglutide:a meta-analysis of clinical trials[J].Diabetes Obes Metab.2013 Feb 22.doi:10.1111/dom.12085.
• [3]Kloneff DC,Buse JB,Nielsen LL,et al.Exanatide effects on diabetes,obesity,cardiovascular risk factors and hepatic biomarkers in patients with type 2 diabetes treated for at least 3 years[J].Curt Med Res Opin,2008,24(1):275.
• [4]Macconell L,Pencek R,Li Y,et al.Exenatide once weekly:sustained improvement in glycomic control end cerdioraetabolic mesenres through 3years[J].Diabetes Metab Syndr Obes,2013,6:31.
• [5]De Messter I,Venhcof G,Hendriks D,et al.Characterization of dipoptidyl peptidase IV(CD26)from human lymphecytes[J].Clin Chim Acta,1992,210(1-2):23.
• [6]Sumitomo M,Shen R,Nenus DM.Involvement of neutral endopoptidase in neoplastic progression[J].Bicohim Biophys Acta,2005,17:51(1):52.
• [7]Orskov C,Wettergren A,Hoist JJ.Biological effects end metabolic rotes of glucagonlike poptide-I 7-36 amide end glucagenlike peptide-1 7-37 in healthy subjects are indistinguishable[J].Diabetes,1993,42(5):6:58.
• [8]Hupe-Sodmenn K,McGregor GP,Bridenbaugh R,et al.Characterisation of the processing by human neutral endopoptidase 24.11 of GLP-1(7-36)amide end comparison of the substrate specificity of the enzyme for other glucagon-like poptides[J].Regul Pept,1995,58(3):149.
• [9]Copley K,McCowen K,Hiles R,et al.Investigation of exenatide elimination end its in vivo and in vitro degradation[J].Curt Drug Metab,2006,7(4):367.
• [10]Linnebjerg H,Kothare PA,Park S,et al.Effect of renal impairment on the pharmacokinetics of exenatide[J].Br J Clin Phannacol,2007,64(3):317.
• [11]Malrn-Erjef(a|¨)lt M,Bj(?)msdottir I,Venggaard J,et al.Metabolism and excretion of the once-daffy human glucagon-like peptide-1 analog liraglutide in healthy male subjects and its in vitro degradation by dipepfidyl peptidase IV end neutral endopeptidase[J].Drug Metab Dispos,2010,38(11):1944
• [12]Rescostock J,Rensch J,Bush M,et al.Potential of albigiutide,a longacting GLP-1 receptor ageuist,in type 2 diabetes:a randomized controlled trial exploring weekly,biweekly,and monthly dosing[J].Diabetes Care,2009,32(10):1880
• [13]Sebokova E,Christ AD,Wang H,et al.Taspoglutide,en analog of human glucagun-like peptide-1 with enhanced stability end in vivo potency[J].Endocrinology,2010,151(6):2474
• [14]Glaeaner W,Vick AM,Millican R,et al.Engineering end characterization of the long-acting glucagen-like poptide-1 analogue LY2189265,an Fc fusion protein[J].Diabetes Metab Res Rev,2010,26(4):287.
• [15]Barnett AH.Lixisenatide:evidence for its potential use in the treatment of type 2 diabetes[J].Core Evid,2011,6:67.
• [16]Baggio LL,Huang Q,Can X,et al.An albumin-exendin-4 conjugate engages central end peripheral circuits regulating mmine energy and glucose homeostasis[J].Gastroenterology,2008,134(4):1137.
• [17]Gong N,Ma AN,Zlieng LJ,et al.Site-specific PEGylation of exenatide analogues markedly improved their glucoregulatory activity[J].Br J Pharmacol,2011,163(2):399.
• [18]Tomas E,Wood JA,Stanojevic V,et al.Glucagon-like poptide-l(9-36)amide metabolite inhibits weight gain end attenuates diabetes and hepatic steatosis in diet-induced obese mice[J].Diabetes Obes Metab,2011,13(1):26.
• [19]Tomas E,Wood JA,Stanojevic V,et al.GLP-l-derived nonapeptide GLP-1(28-36)amide inhibits weight gain and attenuates diabetes and hepatic steatesis in diet-induced obese mice[J].Regul Pept,2011,169(1-3):43.
• [20]N(a|¨)slund E,King N,Mansten S,et al.Prandial subcutaneous injections of glucagen-like peptide-1 cause weight loss in obese human subjeets[J].Br J Nutr,2004,91(3):439
• [21]陈洁,李惟,喻凌,等.合成Exendin-4的体外人血浆稳定性研究[J].高等学校化学学报,2007,28(4):683.
• [22]AI-Sabah S,Dennelly D.A model for receptor-peptide binding at the glucagon-like peptide-1(GLP-1)receptor through the analysis of truncated ligands and receptors[J].Br J Pharmacol,2003,140(2):339.
• [23]Ma X,Hui H,Liu Z,et al.Poly-GLP-1,a novel long-lasting ghcagon-like peptide-1 polymer,ameliorates hyperglycaemia by improving insulin sensitivity and increasing pancreatic beta-cell proliferation[J].Diabetes Obes Metab,2009,1l(10):953.
• [24]周颖,马雪,侯征,等.表达人胰高血糖素样肽前药工程菌遗传稳定性[J].生物加工过程,2010,8(2):61.
• [25]J Vilsbdl T,Kramp T,Sonne J,et a1.Incretin secretion in relation to meal size and body weight.m healthy subjects and people witll type l and type 2 diabetes mellitus[J].J Clin Endocrinol Metab,2003,88(6):2706.
• [26]Grunberger G,Chang A,Gateia Soria G,el a1.Monotherapy wigh the once-weekly GLP-l analogue dulaghtide for 12 weeks.in patients with type 2 diabetes:dose-dependent effects on glycaemic control in a randomized,double-blind,placebo-controlled study[J].Diabet Med,2012,29(10):1260.