A biomimetic approach for enhancing the in vivo half-life of peptides

Nature Chemical Biology
Sravan C PenchalaMamoun M Alhamadsheh

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.

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Methods Mentioned

BETA
surface plasmon resonance
isothermal titration calorimetry
column chromatography
Chip
Assay
saturation binding
ELISA

Software Mentioned

Dock6
Empower
Gaussian
WinNonlin®
Scrubber2
BioLogic
Modeller
GraphPad Prism
Agilent Chemstation

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