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
Since 2005,GLP-1 receptor(GLP-IR)agonists(GLP-IRAs)have been developed as therapeutic agents for type 2 diabetes(T2D).GLP-IR is not only expressed in pancreatic islets but also other organs,especially the lung.However...Since 2005,GLP-1 receptor(GLP-IR)agonists(GLP-IRAs)have been developed as therapeutic agents for type 2 diabetes(T2D).GLP-IR is not only expressed in pancreatic islets but also other organs,especially the lung.However,controversy on extra pancreatic GLP-IR expression still needs to be further resolved,utilizing different tools including the use of more reliable GLP-IR antibodies in immune-staining and co-immune-staining.Extra-pancreatic expression of GLP-IR has triggered extensive investigations on extra-pancreatic functions of GLP-1RAs,aiming to repurpose them into therapeutic agents for other disorders.Extensive studies have demonstrated promising anti-infammatory features of GLP-IRAs.Whether those features are directly mediated by GLP-IR expressed in immune cells also remains controversial.Following a brief review on GLP-1 as an incretin hormone and the development of GLP-IRAs as therapeutic agents for T2D,we have summarized our current understanding of the antiinflammatory features of GLP-IRAS and commented on the controversy on extra-pancreatic GLP-IR expression.The main part of this review is a literature discussion on GLP-IRA utilization in animal models with chronic airway diseases and acute lung injuries,including studies on the combined use of mesenchymal stem cell(MSC)based therapy.This is followed by a brief summary.展开更多
Currently, there is still no effective curative treatment for the development of late-stage liver fibrosis. Here, we have illustrated that TB001, a dual glucagon-like peptide-1 receptor/glucagon receptor(GLP-1 R/GCGR)...Currently, there is still no effective curative treatment for the development of late-stage liver fibrosis. Here, we have illustrated that TB001, a dual glucagon-like peptide-1 receptor/glucagon receptor(GLP-1 R/GCGR) agonist with higher affinity towards GCGR, could retard the progression of liver fibrosis in various rodent models, with remarkable potency, selectivity, extended half-life and low toxicity. Four types of liver fibrosis animal models which were induced by CCl_(4), a-naphthyl-isothiocyanate(ANIT), bile duct ligation(BDL) and Schistosoma japonicum were used in our study. We found that TB001 treatment dose-dependently significantly attenuated liver injury and collagen accumulation in these animal models. In addition to decreased levels of extracellular matrix(ECM) accumulation during hepatic injury, activation of hepatic stellate cells was also inhibited via suppression of TGF-β expression as well as downstream Smad signaling pathways particularly in CCl_(4)-and S. japonicum-induced liver fibrosis. Moreover, TB001 attenuated liver fibrosis through blocking downstream activation of proinflammatory nuclear factor kappa B/NF-kappa-B inhibitor alpha(NFκB/IKBa) pathways as well as cJun N-terminal kinase(JNK)-dependent induction of hepatocyte apoptosis. Furthermore, GLP-1 R and/or GCGR knock-down results represented GCGR played an important role in ameliorating CCl_(4)-induced hepatic fibrosis. Therefore, TB001 can be used as a promising therapeutic candidate for the treatment of multiple causes of hepatic fibrosis demonstrated by our extensive pre-clinical evaluation of TB001.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.
基金supported by the Canadian Institutes of Health Research (PJT159735 to Tianru Jin, Canada)supported by China Scholarship Councilsupported by Ontario Graduate Scholarship (OGS) Program and the Banting & Best Diabetes Centre (BBDC)-Novo Nordisk Studentship
文摘Since 2005,GLP-1 receptor(GLP-IR)agonists(GLP-IRAs)have been developed as therapeutic agents for type 2 diabetes(T2D).GLP-IR is not only expressed in pancreatic islets but also other organs,especially the lung.However,controversy on extra pancreatic GLP-IR expression still needs to be further resolved,utilizing different tools including the use of more reliable GLP-IR antibodies in immune-staining and co-immune-staining.Extra-pancreatic expression of GLP-IR has triggered extensive investigations on extra-pancreatic functions of GLP-1RAs,aiming to repurpose them into therapeutic agents for other disorders.Extensive studies have demonstrated promising anti-infammatory features of GLP-IRAs.Whether those features are directly mediated by GLP-IR expressed in immune cells also remains controversial.Following a brief review on GLP-1 as an incretin hormone and the development of GLP-IRAs as therapeutic agents for T2D,we have summarized our current understanding of the antiinflammatory features of GLP-IRAS and commented on the controversy on extra-pancreatic GLP-IR expression.The main part of this review is a literature discussion on GLP-IRA utilization in animal models with chronic airway diseases and acute lung injuries,including studies on the combined use of mesenchymal stem cell(MSC)based therapy.This is followed by a brief summary.
基金the financial support from the National Natural Science Foundation of China (No.91853106)the Program for Guangdong Introducing Innovative and Enterpre-neurial Teams (No.2016ZT06Y337,China)+3 种基金Guangdong Provincial Key Laboratory of Construction Foundation (No.2019B030301005,China)Shenzhen Science and Technology Program (JSGG20200225153121723,China)the Fundamental Research Funds for the Central Universities (No.19ykzd25,China)CAMS Innovation Fund for Medical Sciences (CIFMS,2019-I2M-5-074,China)。
文摘Currently, there is still no effective curative treatment for the development of late-stage liver fibrosis. Here, we have illustrated that TB001, a dual glucagon-like peptide-1 receptor/glucagon receptor(GLP-1 R/GCGR) agonist with higher affinity towards GCGR, could retard the progression of liver fibrosis in various rodent models, with remarkable potency, selectivity, extended half-life and low toxicity. Four types of liver fibrosis animal models which were induced by CCl_(4), a-naphthyl-isothiocyanate(ANIT), bile duct ligation(BDL) and Schistosoma japonicum were used in our study. We found that TB001 treatment dose-dependently significantly attenuated liver injury and collagen accumulation in these animal models. In addition to decreased levels of extracellular matrix(ECM) accumulation during hepatic injury, activation of hepatic stellate cells was also inhibited via suppression of TGF-β expression as well as downstream Smad signaling pathways particularly in CCl_(4)-and S. japonicum-induced liver fibrosis. Moreover, TB001 attenuated liver fibrosis through blocking downstream activation of proinflammatory nuclear factor kappa B/NF-kappa-B inhibitor alpha(NFκB/IKBa) pathways as well as cJun N-terminal kinase(JNK)-dependent induction of hepatocyte apoptosis. Furthermore, GLP-1 R and/or GCGR knock-down results represented GCGR played an important role in ameliorating CCl_(4)-induced hepatic fibrosis. Therefore, TB001 can be used as a promising therapeutic candidate for the treatment of multiple causes of hepatic fibrosis demonstrated by our extensive pre-clinical evaluation of TB001.
