A Biomimetic Approach for Enhancing the in Vivo Half-Life of Peptides

Nat Chem Biol. 2015 Oct;11(10):793-8. doi: 10.1038/nchembio.1907. Epub 2015 Sep 7.

Abstract

The tremendous therapeutic potential of peptides has not yet been realized, mainly owing to their short in vivo half-life. Although conjugation to macromolecules has been a mainstay approach for enhancing protein half-life, the steric hindrance of macromolecules often harms the binding of peptides to target receptors, compromising the in vivo efficacy. Here we report a new strategy for enhancing the in vivo half-life of peptides without compromising their potency. Our approach involves endowing peptides with a small molecule that binds reversibly to the serum protein transthyretin. Although there are a few molecules that bind albumin reversibly, we are unaware of designed small molecules that reversibly bind other serum proteins and are used for half-life extension in vivo. We show here that our strategy was effective in enhancing the half-life of an agonist for GnRH receptor while maintaining its binding affinity, which was translated into superior in vivo efficacy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Benzoates / blood
  • Benzoates / chemistry*
  • Benzoates / metabolism
  • Benzoates / pharmacology
  • Binding Sites
  • Biomimetics / methods*
  • Cell Survival / drug effects
  • Half-Life
  • HeLa Cells
  • Humans
  • Ligands
  • Male
  • Microsomes, Liver / metabolism
  • Models, Molecular
  • Molecular Docking Simulation
  • Molecular Sequence Data
  • Peptide Fragments / blood
  • Peptide Fragments / chemistry*
  • Peptide Fragments / metabolism
  • Peptide Fragments / pharmacology
  • Prealbumin / chemistry*
  • Prealbumin / metabolism
  • Prealbumin / pharmacology
  • Protein Binding
  • Protein Stability
  • Pyrazoles / blood
  • Pyrazoles / chemistry*
  • Pyrazoles / metabolism
  • Pyrazoles / pharmacology
  • Rats, Sprague-Dawley
  • Rats, Wistar
  • Receptors, LHRH / agonists*

Substances

  • 3-(3-(3,5-dimethyl-1H-pyrazol-4-yl)propoxy)-4-fluorobenzoic acid
  • Benzoates
  • Ligands
  • Peptide Fragments
  • Prealbumin
  • Pyrazoles
  • Receptors, LHRH

Associated data

  • PubChem-Substance/252165695
  • PubChem-Substance/252165696
  • PubChem-Substance/252165697
  • PubChem-Substance/252165698
  • PubChem-Substance/252165699
  • PubChem-Substance/252165700
  • PubChem-Substance/252165701
  • PubChem-Substance/252165702
  • PubChem-Substance/252165703
  • PubChem-Substance/252165704
  • PubChem-Substance/252165705
  • PubChem-Substance/252165706
  • PubChem-Substance/252165707
  • PubChem-Substance/252165708
  • PubChem-Substance/252165709
  • PubChem-Substance/252165710
  • PubChem-Substance/252165711