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BACKGROUND AND PURPOSE: Incretin-based therapies based on glucagon-like peptide-1 (GLP-1) receptor agonists are effective treatments of type 2 diabetes. Abundant research has focused on the development of long-acting GLP-1 receptor agonists. However, all GLP-1 receptor agonists in clinical use or development are based on human or Gila GLP-1. We have identified a potent GLP-1 receptor agonist, xGLP-1B, based on Xenopus GLP-1.
EXPERIMENTAL APPROACH: To further modify the structure of xGLP-1B, alanine scanning was performed to study the structure -activity relationship of xGLP-1B. Two strategies were then employed to improve bioactivity. First, the C-terminal tail of lixisenatide was appended to cysteine-altered xGLP-1B analogues. Second, polyethylene glycol (PEG) chains with different molecular weights were conjugated with the peptides, giving a series of PEGylated conjugates. Comprehensive bioactivity studies of these conjugates were performed in vitro and in vivo.
RESULTS: From the in vitro receptor activation potency and in vivo acute hypoglycaemic activities of conjugates 25 -36, 33 was identified as the best candidate for further biological assessments. Conjugate 33 exhibited prominent hypoglycaemic and insulinotropic activities, as well as improved pharmacokinetic profiles in vivo. The prolonged antidiabetic duration of 33 was further confirmed by pre-oral glucose tolerance tests (OGTT) and multiple OGTT. Furthermore, chronic treatment of db/db mice with 33 ameliorated non-fasting blood glucose and insulin levels, reduced HbA1c values and normalized their impaired glucose tolerance. Importantly, no in vivo toxicity was observed in mice treated with 33.
CONCLUSIONS AND IMPLICATIONS: Peptide 33 is a promising long-acting type 2 diabetes therapeutic deserving further investigation.
Adelhorst,
Structure-activity studies of glucagon-like peptide-1.
1994, Pubmed
Adelhorst,
Structure-activity studies of glucagon-like peptide-1.
1994,
Pubmed
Agyemang,
Obesity and type 2 diabetes in sub-Saharan Africans - Is the burden in today's Africa similar to African migrants in Europe? The RODAM study.
2016,
Pubmed
Alexander,
THE CONCISE GUIDE TO PHARMACOLOGY 2017/18: G protein-coupled receptors.
2017,
Pubmed
Bianchi,
A PEGylated analog of the gut hormone oxyntomodulin with long-lasting antihyperglycemic, insulinotropic and anorexigenic activity.
2013,
Pubmed
Curtis,
Experimental design and analysis and their reporting: new guidance for publication in BJP.
2015,
Pubmed
Evers,
Design of Novel Exendin-Based Dual Glucagon-like Peptide 1 (GLP-1)/Glucagon Receptor Agonists.
2017,
Pubmed
Fonseca,
Efficacy and safety of the once-daily GLP-1 receptor agonist lixisenatide in monotherapy: a randomized, double-blind, placebo-controlled trial in patients with type 2 diabetes (GetGoal-Mono).
2012,
Pubmed
Hager,
Characterization of signal bias at the GLP-1 receptor induced by backbone modification of GLP-1.
2017,
Pubmed
Han,
Novel fatty chain-modified glucagon-like peptide-1 conjugates with enhanced stability and prolonged in vivo activity.
2013,
Pubmed
Han,
Design, synthesis, and biological activity of novel dicoumarol glucagon-like peptide 1 conjugates.
2013,
Pubmed
Han,
Xenopus-derived glucagon-like peptide-1 and polyethylene-glycosylated glucagon-like peptide-1 receptor agonists: long-acting hypoglycaemic and insulinotropic activities with potential therapeutic utilities.
2018,
Pubmed
,
Xenbase
Han,
Novel coumarin modified GLP-1 derivatives with enhanced plasma stability and prolonged in vivo glucose-lowering ability.
2014,
Pubmed
Han,
Design, synthesis and biological evaluation of PEGylated Xenopus glucagon-like peptide-1 derivatives as long-acting hypoglycemic agents.
2017,
Pubmed
,
Xenbase
Irwin,
The Xenopus proglucagon gene encodes novel GLP-1-like peptides with insulinotropic properties.
1997,
Pubmed
,
Xenbase
Kerr,
Effects of gamma-glutamyl linker on DPP-IV resistance, duration of action and biological efficacy of acylated glucagon-like peptide-1.
2010,
Pubmed
Kilkenny,
Animal research: reporting in vivo experiments: the ARRIVE guidelines.
2010,
Pubmed
Kim,
Mono-PEGylated dimeric exendin-4 as high receptor binding and long-acting conjugates for type 2 anti-diabetes therapeutics.
2011,
Pubmed
Kompella,
Alanine scan of α-conotoxin RegIIA reveals a selective α3β4 nicotinic acetylcholine receptor antagonist.
2015,
Pubmed
,
Xenbase
Manandhar,
Glucagon-like peptide-1 (GLP-1) analogs: recent advances, new possibilities, and therapeutic implications.
2015,
Pubmed
Mapelli,
Eleven amino acid glucagon-like peptide-1 receptor agonists with antidiabetic activity.
2009,
Pubmed
McGrath,
Implementing guidelines on reporting research using animals (ARRIVE etc.): new requirements for publication in BJP.
2015,
Pubmed
Meier,
GLP-1 receptor agonists for individualized treatment of type 2 diabetes mellitus.
2012,
Pubmed
Mishra,
Relative contribution of type 1 and type 2 diabetes loci to the genetic etiology of adult-onset, non-insulin-requiring autoimmune diabetes.
2017,
Pubmed
Murage,
Development of potent glucagon-like peptide-1 agonists with high enzyme stability via introduction of multiple lactam bridges.
2010,
Pubmed
Nathan,
Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes.
2009,
Pubmed
Southan,
The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands.
2016,
Pubmed
Sun,
Site-specific fatty chain-modified exenatide analogs with balanced glucoregulatory activity and prolonged in vivo activity.
2016,
Pubmed
Tomlinson,
An overview of new GLP-1 receptor agonists for type 2 diabetes.
2016,
Pubmed
van Witteloostuijn,
Neoglycolipids for Prolonging the Effects of Peptides: Self-Assembling Glucagon-like Peptide 1 Analogues with Albumin Binding Properties and Potent in Vivo Efficacy.
2017,
Pubmed
van Witteloostuijn,
Half-Life Extension of Biopharmaceuticals using Chemical Methods: Alternatives to PEGylation.
2016,
Pubmed
Yang,
Design, synthesis and biological evaluation of novel peptide MC2 analogues from Momordica charantia as potential anti-diabetic agents.
2015,
Pubmed
Yang,
Long-acting GLP-1 analogue in V-shaped conformation by terminal polylysine modifications.
2014,
Pubmed
