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

• Published in: Nature chemical biology Vol. 11; no. 10; pp. 793 - 798
• Main Authors: Penchala, Sravan C, Miller, Mark R, Pal, Arindom, Dong, Jin, Madadi, Nikhil R, Xie, Jinghang, Joo, Hyun, Tsai, Jerry, Batoon, Patrick, Samoshin, Vyacheslav, Franz, Andreas, Cox, Trever, Miles, Jesse, Chan, William K, Park, Miki S, Alhamadsheh, Mamoun M
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01-10-2015; Nature Publishing Group
• Subjects: 631/92/152; 631/92/436; 631/92/611; 631/92/95; Amino Acid Sequence; Amino acids; Animals; Benzoates - blood; Benzoates - chemistry; Benzoates - metabolism; Benzoates - pharmacology; Binding Sites; Biochemical Engineering; Biochemistry; Biomimetics; Biomimetics - methods; Bioorganic Chemistry; Cell Biology; Cell Survival - drug effects; Chemistry; Chemistry/Food Science; Half-Life; HeLa Cells; Humans; Ligands; Male; Microsomes, Liver - metabolism; Models, Molecular; Molecular Docking Simulation; Molecular Sequence Data; Molecules; Peptide Fragments - blood; Peptide Fragments - chemistry; Peptide Fragments - metabolism; Peptide Fragments - pharmacology; Peptides; Prealbumin - chemistry; Prealbumin - metabolism; Prealbumin - pharmacology; Protein Binding; Protein Stability; Pyrazoles - blood; Pyrazoles - chemistry; Pyrazoles - metabolism; Pyrazoles - pharmacology; Rats, Sprague-Dawley; Rats, Wistar; Receptors, LHRH - agonists
• ISSN: 1552-4450; 1552-4469
• DOI: 10.1038/nchembio.1907

Linking a peptide with a small-molecule ligand for the serum protein transthyretin ensures half-life extension without diminishing potency through protection against proteases and decreasing glomerular filtration.
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.