A biomimetic approach for enhancing the in vivo half-life of peptides.
Nat Chem Biol
; 11(10): 793-8, 2015 Oct.
Article
in En
| MEDLINE
| ID: mdl-26344696
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Peptide Fragments
/
Pyrazoles
/
Benzoates
/
Prealbumin
/
Receptors, LHRH
/
Biomimetics
Limits:
Animals
/
Humans
/
Male
Language:
En
Journal:
Nat Chem Biol
Year:
2015
Document type:
Article