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Single Peptide Backbone Surrogate Mutations to Regulate Angiotensin GPCR Subtype Selectivity.

Eirinaios I Vrettos1, Ibai E Valverde2,3, Alba Mascarin2

  • 1Department of Chemistry, University of Ioannina, Ioannina, 45110, Greece.

Chemistry (Weinheim an Der Bergstrasse, Germany)
|July 22, 2020
PubMed
Summary

Replacing peptide bonds with triazole bioisosters enhances peptide stability and receptor selectivity. One analogue showed improved neurotrophic potential, promoting neurite growth more effectively than existing agents.

Keywords:
G-protein-coupled receptorsclick chemistrycompetition-binding experimentsneurotrophic effectspeptidomimetics

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Area of Science:

  • Medicinal Chemistry
  • Peptide Chemistry
  • Neuroscience

Background:

  • Peptide ligands often suffer from short half-lives due to proteolytic degradation.
  • Modifying peptide backbones with bioisosters offers a strategy to improve stability and potentially modulate receptor interactions.
  • Angiotensin II analogues are crucial for studying cardiovascular and neurological functions.

Purpose of the Study:

  • To synthesize [Y]6-Angiotensin II analogues by replacing backbone amide bonds with 1,2,3-triazole bioisosters.
  • To evaluate the impact of these modifications on proteolytic stability, AT2 R/AT1 R subtype selectivity, and neurotrophic potential.

Main Methods:

  • Synthesis of four [Y]6-Angiotensin II analogues with triazole isosteres at different backbone positions.
  • Assessment of plasma stability and receptor subtype selectivity (AT2 R/AT1 R).
  • Structural elucidation using 2D NMR spectroscopy and evaluation of neurotrophic activity.

Main Results:

  • All synthesized analogues exhibited enhanced stability in human plasma compared to the parent peptide.
  • Two analogues demonstrated improved AT2 R/AT1 R subtype selectivity.
  • 2D NMR revealed a more structured conformation for selective analogues, indicated by increased NOE cross-peaks.
  • The most potent analogue (compound 2) significantly enhanced neurite outgrowth.

Conclusions:

  • 1,2,3-triazole bioisosters effectively enhance the stability of [Y]6-Angiotensin II analogues.
  • Backbone modification can tune receptor subtype selectivity and improve pharmacokinetic properties.
  • The lead analogue shows promise as a neurotrophic agent for potential therapeutic applications.