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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This work was supported by a New Investigator Award from the American Association of Colleges of Pharmacy and the US National Institutes of Health grant 1R15GM110677-01 (M.M.A.). The support by a National Science Foundation Instrumentation grant (NSF-MRI-0722654) is gratefully acknowledged.
The co-authors have filed a provisional patent application related to this work.
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Penchala, S., Miller, M., Pal, A. et al. A biomimetic approach for enhancing the in vivo half-life of peptides. Nat Chem Biol 11, 793–798 (2015). https://doi.org/10.1038/nchembio.1907
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