Peptides are increasingly important resources for biological and therapeutic development,however,their intrinsic susceptibility to proteolytic degradation represents a big hurdle.As a natural agonist for GLP-1R,glucag...Peptides are increasingly important resources for biological and therapeutic development,however,their intrinsic susceptibility to proteolytic degradation represents a big hurdle.As a natural agonist for GLP-1R,glucagon-like peptide 1(GLP-1)is of significant clinical interest for the treatment of type-2 diabetes mellitus,but its in vivo instability and short half-life have largely prevented its therapeutic application.Here,we describe the rational design of a series of a/sulfono-γ-AA peptide hybrid analogues of GLP-1 as the GLP-1R agonists.Certain GLP-1 hybrid analogues exhibited enhanced stability(t_(1/2)>14 days)compared to t_(1/2)(<1 day)of GLP-1 in the blood plasma and in vivo.These newly developed peptide hybrids may be viable alternative of semaglutide for type-2 diabetes treatment.Additionally,our findings suggest that sulfono-γ-AA residues could be adopted to substitute canonical amino acids residues to improve the pharmacological activity of peptide-based drugs.展开更多
Glucagon-like peptide-1 receptor （GLP-1R） agonists are widely used for treating type 2 diabetes mellitus （T2DM） be- cause of their glucose-lowering and weight-losing effects, and low risk of hypoglycemia. Hence, t...Glucagon-like peptide-1 receptor （GLP-1R） agonists are widely used for treating type 2 diabetes mellitus （T2DM） be- cause of their glucose-lowering and weight-losing effects, and low risk of hypoglycemia. Hence, there is considerable interest in understanding the mechanism underlying the beneficial effects of GLP-I and developing stable and effective GLP-1R agonists. Here, we summarize the presently known mechanism of GLP-I actions, which are mainly through regulating cAMP-PKA signaling pathway; the latest developments in novel clinical GLP-1R agonists are also introduced, which are characterized with multiple properties, such as extended half-life, reduced side-effects, lower production costs and more convenient drug dosing mode. The potential risk of GLP-I-based therapeutics, an often-ignored fact, is also discussed.展开更多
基金supported by NIH R01AI152416(to Jianfeng Cai,USA)NIH R01 AG056569(to Jianfeng Cai,USA)。
文摘Peptides are increasingly important resources for biological and therapeutic development,however,their intrinsic susceptibility to proteolytic degradation represents a big hurdle.As a natural agonist for GLP-1R,glucagon-like peptide 1(GLP-1)is of significant clinical interest for the treatment of type-2 diabetes mellitus,but its in vivo instability and short half-life have largely prevented its therapeutic application.Here,we describe the rational design of a series of a/sulfono-γ-AA peptide hybrid analogues of GLP-1 as the GLP-1R agonists.Certain GLP-1 hybrid analogues exhibited enhanced stability(t_(1/2)>14 days)compared to t_(1/2)(<1 day)of GLP-1 in the blood plasma and in vivo.These newly developed peptide hybrids may be viable alternative of semaglutide for type-2 diabetes treatment.Additionally,our findings suggest that sulfono-γ-AA residues could be adopted to substitute canonical amino acids residues to improve the pharmacological activity of peptide-based drugs.
基金Supported by the Natural Science Foundation of China(81172971,81222043)the Program for New Century Excellent Talents in University(NECT11-0170)+2 种基金the Municiple Key Technology Program of Wuhan(Wuhan Bureau of Science & Technology,201260523174)the Clinical Research Foundation of the Health Bureau of Wuhan(WX12B06)the Natural Science Foundation of Hubei Province(2013CFB359)
文摘Glucagon-like peptide-1 receptor （GLP-1R） agonists are widely used for treating type 2 diabetes mellitus （T2DM） be- cause of their glucose-lowering and weight-losing effects, and low risk of hypoglycemia. Hence, there is considerable interest in understanding the mechanism underlying the beneficial effects of GLP-I and developing stable and effective GLP-1R agonists. Here, we summarize the presently known mechanism of GLP-I actions, which are mainly through regulating cAMP-PKA signaling pathway; the latest developments in novel clinical GLP-1R agonists are also introduced, which are characterized with multiple properties, such as extended half-life, reduced side-effects, lower production costs and more convenient drug dosing mode. The potential risk of GLP-I-based therapeutics, an often-ignored fact, is also discussed.
文摘目的:建立测定米拉贝隆原料中有关物质的方法。方法:采用HPLC方法分离分析米拉贝隆的有关物质,使用Cosmosil C18(250 mm×4.6 mm,5μm)色谱柱;流动相A为10 mmol·L^(-1)庚烷磺酸钠+20 mmol·L^(-1)磷酸二氢钾溶液(用磷酸调至p H 3.0)-乙腈(90∶10),流动相B为乙腈,梯度洗脱,流速1.0 m L·min^(-1),检测波长220 nm,柱温35℃;采用流动相A为0.1%乙酸(用氨水调至p H 3.0)-乙腈(90∶10),流动相B为乙腈,梯度洗脱,利用LC-MS/MS方法进行鉴别。结果:米拉贝隆与有关物质均能有效分离;LC-MS/MS鉴定了3种主要降解产物:杂质a(2-氨基噻唑-4-乙酸,化合物4)、杂质b((R)-2-[[[2-(4-氨基苯基)乙基]氨基]甲基]苯甲醇,化合物8)和杂质c(2-(2-氨基噻唑-4-基)-N-[4-[2-(苯基乙基氨基)乙基]苯基]乙酰胺,化合物9)的定量限分别为7.02、7.32和9.18 ng,且在各自的线性范围内线性关系良好(r=1.000、0.999 0、1.000,n=5);校正因子分别为1.4、1.6和1.3。结论:建立的方法可对米拉贝隆的有关物质进行定量测定。
