Journal
NATURE CHEMICAL BIOLOGY
Volume 11, Issue 10, Pages 793-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/NCHEMBIO.1907
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Funding
- New Investigator Award from the American Association of Colleges of Pharmacy
- US National Institutes of Health [1R15GM110677-01]
- National Science Foundation Instrumentation grant [NSF-MRI-0722654]
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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 macro-molecules 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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