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Design of potent and proteolytically stable oxyntomodulin analogs

Academic Article
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Overview

authors

  • Muppidi, A.
  • Zou, H.
  • Yang, P. Y.
  • Chao, E.
  • Sherwood, L.
  • Nunez, V.
  • Woods, A. K.
  • Schultz, Peter
  • Lin, Q.
  • Shen, W.

publication date

  • February 2016

journal

  • ACS Chemical Biology  Journal

abstract

  • Incretin-based peptides are effective therapeutics for treating type 2 diabetes mellitus (T2DM). Oxyntomodulin (OXM), a dual agonist of GLP-1R and GCGR, has shown superior weight loss and glucose lowering effects, compared to single GLP-1R agonists. To overcome the short half-life and rapid renal clearance of OXM, which limit its therapeutic potential, both lipid and PEG modified OXM analogs have been reported. However, these approaches often result in reduced potency or PEG-associated toxicity. Herein, we report a new class of cross-linked OXM analogs that show increased plasma stability and higher potency in activating both GLP-1R and GCGR. Moreover, the extended in vivo half-life results in superior antihyperglycemic activity in mice compared to the wild-type OXM.

subject areas

  • Amino Acid Sequence
  • Animals
  • Cross-Linking Reagents
  • Glucagon-Like Peptide-1 Receptor
  • HEK293 Cells
  • Humans
  • Hypoglycemic Agents
  • Mice
  • Models, Molecular
  • Molecular Sequence Data
  • Oxyntomodulin
  • Proteolysis
  • Receptors, Glucagon
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Identity

PubMed Central ID

  • PMC4861236

International Standard Serial Number (ISSN)

  • 1554-8929

Digital Object Identifier (DOI)

  • 10.1021/acschembio.5b00787

PubMed ID

  • 26727558
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Additional Document Info

start page

  • 324

end page

  • 328

volume

  • 11

issue

  • 2

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