Design, synthesis and biological evaluation of PEGylated Xenopus glucagon-like peptide-1 derivatives as long-acting hypoglycemic agents.

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  • Additional Information
    • Source:
      Publisher: Editions Scientifiques Elsevier Country of Publication: France NLM ID: 0420510 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1768-3254 (Electronic) Linking ISSN: 02235234 NLM ISO Abbreviation: Eur J Med Chem Subsets: MEDLINE
    • Publication Information:
      Publication: Paris : Editions Scientifiques Elsevier
      Original Publication: Paris, S.E.C.T. [etc.]
    • Subject Terms:
      Diabetes Mellitus, Type 2/*drug therapy ; Glucagon-Like Peptide 1/*chemistry ; Hypoglycemic Agents/*chemical synthesis ; Hypoglycemic Agents/*pharmacokinetics ; Polyethylene Glycols/*chemistry; Animals ; Blood Glucose/drug effects ; Cysteine/genetics ; Drug Design ; Glucagon-Like Peptide 1/pharmacology ; Half-Life ; Humans ; Hypoglycemic Agents/pharmacology ; Insulin/blood ; Mice, Inbred Strains ; Mutagenesis, Site-Directed ; Mutant Chimeric Proteins/pharmacology ; Polyethylene Glycols/pharmacology ; Xenopus
    • Abstract:
      In order to develop novel long-acting GLP-1 derivatives, a peptide hybrid (1a) from human GLP-1 and Xenopus GLP-1 discovered in our previous research was selected as the lead compound. Exendin-4 inspired modification resulted in peptide 1b with enhanced glucose-lowering activity. Cysteine mutated 1b derivatives with reserved bioactivity were further site-specifically connected with mPEG 2000 -MAL to provide conjugates 3a-h, among which 3d and 3e were found to have significantly improved hypoglycemic activity and insulinotropic ability than GLP-1. The hypoglycemic durations of 3d and 3e were remarkably prolonged to ∼20 h in type 2 diabetic db/db mice, compared with the 5.3 h of exendin-4 in the same test. Finally, chronic in vivo studies revealed that a once-daily treatment of 3d or 3e for five weeks resulted in recovered glucose-controlling ability of type 2 diabetic db/db mice, along with other benefits, such as reduced body weight gains, food intake amounts and HbA1c values. Collectively, our results suggest 3d and 3e as potential long-acting glucose-lowering agents for treating type 2 diabetes.
      (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)
    • Contributed Indexing:
      Keywords: Glucagon-like peptide-1; PEGylation; Type 2 diabetes
    • Accession Number:
      0 (Blood Glucose)
      0 (Hypoglycemic Agents)
      0 (Insulin)
      0 (Mutant Chimeric Proteins)
      3WJQ0SDW1A (Polyethylene Glycols)
      89750-14-1 (Glucagon-Like Peptide 1)
      K848JZ4886 (Cysteine)
    • Publication Date:
      Date Created: 20170326 Date Completed: 20170605 Latest Revision: 20181202
    • Publication Date:
      20240628
    • Accession Number:
      10.1016/j.ejmech.2017.03.032
    • Accession Number:
      28342399