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

Citation data:

Nature chemical biology, ISSN: 1552-4469, Vol: 11, Issue: 10, Page: 793-8

Publication Year:
2015
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Repository URL:
https://works.bepress.com/andreas-franz/57; https://scholarlycommons.pacific.edu/cop-facarticles/117
PMID:
26344696
DOI:
10.1038/nchembio.1907
PMCID:
PMC4575266
Author(s):
Penchala, Sravan C.; Miller, Mark R.; Pal, Arindom; Dong, Jin; Madadi, Nikhil R.; Xie, Jinghang; Joo, Hyun; Tsai, Jerry; Batoon, Patrick; Samoshin, Vyacheslav V.; Franz, Andreas H.; Cox, Trevor; Miles, Jesse; Chan, William K.; Park, Miki S.; Alhamadsheh, Mamoun M Show More Hide
Publisher(s):
Springer Nature
Tags:
Biochemistry, Genetics and Molecular Biology; drug delivery; peptides; pharmacology; chemical synthesis; Chemistry
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article description
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.