Pharmacological characterization of mono-, dual- and tri-peptidic agonists at GIP and GLP-1 receptors

May 4, 2020Biochemical pharmacology

Drug effects of single, double, and triple peptide activators on GIP and GLP-1 hormone receptors

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Abstract

GIP receptor mono-agonists show biased signaling towards ERK1/2 phosphorylation compared to cAMP accumulation.

  • GIP-dependent insulinotropic peptide signaling plays roles in various physiological processes including fat storage and bone health.
  • Selective ligands for the GIP receptor have not yet been developed for treating diseases.
  • Dual and triple agonists targeting GIPR, GLP-1R, and glucagon receptors are under clinical investigation for improved efficacy in diabetes management.
  • The GIPR mono-agonists Pro3GIP and Lys3GIP exhibit preferential signaling towards ERK1/2 activation over cAMP production.
  • The triple agonist at GLP-1R, GCGR, and GIPR favors ERK1/2 activation relative to Ī²-arrestin2 recruitment.
  • The dual GIPR/GLP-1R agonist LY3298176 also demonstrates biased signaling towards ERK1/2 activation compared to cAMP at both receptors.

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