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Tytuł:
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Design and characterization of novel oxyntomodulin derivatives with potent dual GLP-1/glucagon receptor activation and prolonged antidiabetic effects.
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Autorzy:
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Pei Z; College of Animal Sciences, Zhejiang University, Hangzhou 310058, PR China; Hangzhou RunChongGuiMei Bio-tech Co., Ltd., Xiao Shan, Hangzhou 310058, PR China. Electronic address: .
Zhou D; National Research Center for Veterinary Medicine, Road Cuiwei, High-Tech District, Luoyang 471003, PR China.
Yan J; Suzhou Xishan Zhongke Drug R&D Co., Ltd., Wuzhong Avenue, Suzhou 215000, PR China.
Wang S; College of Animal Sciences, Zhejiang University, Hangzhou 310058, PR China.
Yang X; Hangzhou RunChongGuiMei Bio-tech Co., Ltd., Xiao Shan, Hangzhou 310058, PR China.
Pei Z; Hangzhou RunChongGuiMei Bio-tech Co., Ltd., Xiao Shan, Hangzhou 310058, PR China.
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Źródło:
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Life sciences [Life Sci] 2020 Jul 15; Vol. 253, pp. 117651. Date of Electronic Publication: 2020 Apr 15.
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Typ publikacji:
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Journal Article
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Język:
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English
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Imprint Name(s):
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Publication: <2008->: Amsterdam : Elsevier
Original Publication: Oxford; Elmsford, N. Y. [etc.] Pergamon Press.
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MeSH Terms:
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Glucagon-Like Peptide-1 Receptor/*metabolism
Hypoglycemic Agents/*chemistry
Oxyntomodulin/*chemistry
Receptors, Glucagon/*metabolism
Animals ; Blood Glucose/drug effects ; Diabetes Mellitus/metabolism ; Dimerization ; Glucagon/metabolism ; Glucose Tolerance Test ; Hypoglycemic Agents/pharmacokinetics ; Macaca fascicularis ; Male ; Mice ; Mice, Knockout ; Mice, Obese ; Obesity/metabolism ; Oxyntomodulin/pharmacokinetics ; Polyethylene Glycols/chemistry ; Rats, Sprague-Dawley ; Solid-Phase Synthesis Techniques ; Weight Loss/drug effects
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Contributed Indexing:
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Keywords: Diabetes; Dimerization; GLP-1; Glucagon; Obesity; Oxyntomodulin; PEGylation
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Substance Nomenclature:
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0 (Blood Glucose)
0 (Glucagon-Like Peptide-1 Receptor)
0 (Hypoglycemic Agents)
0 (Oxyntomodulin)
0 (Receptors, Glucagon)
3WJQ0SDW1A (Polyethylene Glycols)
9007-92-5 (Glucagon)
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Entry Date(s):
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Date Created: 20200419 Date Completed: 20200615 Latest Revision: 20200615
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Update Code:
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20240104
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DOI:
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10.1016/j.lfs.2020.117651
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PMID:
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32304764
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Aims: To investigate the combination of dimerization and PEGylation to enhance the receptor activation and in vivo stability of Oxyntomodulin (OXM).
Main Methods: All LDM peptides were produced by using standard method of solid phase synthesis. The in vitro effects of LDM peptides were assessed by glucagon-like peptide-1 receptor (GLP-1R) and glucagon receptor (GcgR) binding test and Proteolytic stability test. Subsequently, saline, Liraglutide and three doses of LDM-3 treated groups were subjected to the evaluation of aute and long-term efficacy.
Key Findings: Five long-acting OXM conjugates, termed LDM-1 to LDM-5, were designed using cysteine (Cys)-specific modification reaction including the activated PEG, bisMal-NH 2 , and OXM-Cys, and all prepared with high purity. LDM-3 exhibited greater GLP-1R and GcgR activation and ameliorative serum stability. In addition, LDM-3 was identified with enhanced insulinotropic and glycemic abilities in the gene knockout mice. The prolonged glucose-lowering effects of the LDM-3 were proved by hypoglycemic duration test and multiple oral glucose tolerance tests (OGTTs) in the diet-induced obesity (DIO) mice. Furthermore, the pharmacokinetic tests in Sprague Dawley (SD) rat and cynomolgus monkey exhibited the lifespans of LDM-3 at 90 nmol·kg -1 were 101.5 h and 119.4 h, respectively. Nevertheless, consecutive 8-week administration of LDM-3 improved the cumulative body weight gain, food intake, % HbA1c, glucose tolerance and the pancreatic of the obese mice.
Significance: LDM-3, as a dual GLP-1R and GcgR agonist, holds potential to be developed as a promising therapeutic candidate for both diabetes and obesity.
Competing Interests: Declaration of competing interest The authors declare no conflict of interest.
(Copyright © 2020 Elsevier Inc. All rights reserved.)
