A biomimetic approach for enhancing the in vivo half-life of peptides.
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.
Department of Pharmaceutics &Medicinal Chemistry, Thomas J. Long School of Pharmacy &Health Sciences, University of the Pacific, Stockton, California, USA.
Sravan C
SC
Penchala
Department of Pharmaceutics &Medicinal Chemistry, Thomas J. Long School of Pharmacy &Health Sciences, University of the Pacific, Stockton, California, USA.
Mark R
MR
Miller
Department of Pharmaceutics &Medicinal Chemistry, Thomas J. Long School of Pharmacy &Health Sciences, University of the Pacific, Stockton, California, USA.
Arindom
A
Pal
Department of Pharmaceutics &Medicinal Chemistry, Thomas J. Long School of Pharmacy &Health Sciences, University of the Pacific, Stockton, California, USA.
Jin
J
Dong
Department of Pharmaceutics &Medicinal Chemistry, Thomas J. Long School of Pharmacy &Health Sciences, University of the Pacific, Stockton, California, USA.
Nikhil R
NR
Madadi
Department of Pharmaceutics &Medicinal Chemistry, Thomas J. Long School of Pharmacy &Health Sciences, University of the Pacific, Stockton, California, USA.
Jinghang
J
Xie
Department of Chemistry, University of the Pacific, Stockton, California, USA.
Hyun
H
Joo
Department of Chemistry, University of the Pacific, Stockton, California, USA.
Jerry
J
Tsai
Department of Chemistry, University of the Pacific, Stockton, California, USA.
Patrick
P
Batoon
Department of Chemistry, University of the Pacific, Stockton, California, USA.
Vyacheslav
V
Samoshin
Department of Chemistry, University of the Pacific, Stockton, California, USA.
Andreas
A
Franz
Department of Pharmaceutics &Medicinal Chemistry, Thomas J. Long School of Pharmacy &Health Sciences, University of the Pacific, Stockton, California, USA.
Trever
T
Cox
Department of Pharmaceutics &Medicinal Chemistry, Thomas J. Long School of Pharmacy &Health Sciences, University of the Pacific, Stockton, California, USA.
Jesse
J
Miles
Department of Pharmaceutics &Medicinal Chemistry, Thomas J. Long School of Pharmacy &Health Sciences, University of the Pacific, Stockton, California, USA.
William K
WK
Chan
Department of Pharmaceutics &Medicinal Chemistry, Thomas J. Long School of Pharmacy &Health Sciences, University of the Pacific, Stockton, California, USA.
Miki S
MS
Park
Department of Pharmaceutics &Medicinal Chemistry, Thomas J. Long School of Pharmacy &Health Sciences, University of the Pacific, Stockton, California, USA.
Mamoun M
MM
Alhamadsheh
D000595:Amino Acid Sequence; D000818:Animals; D001565:Benzoates / Q000097:blood / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D001665:Binding Sites; D032701:Biomimetics / Q000379:methods*; D002470:Cell Survival / Q000187:drug effects; D006207:Half-Life; D006367:HeLa Cells; D006801:Humans; D008024:Ligands; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000097:blood / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D011228:Prealbumin / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D011485:Protein Binding; D055550:Protein Stability; D011720:Pyrazoles / Q000097:blood / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D011966:Receptors, LHRH / Q000819:agonists*; D019817:Benzoic Acid
D001565:Benzoates; D008024:Ligands; D010446:Peptide Fragments; D011228:Prealbumin; D011720:Pyrazoles; D011966:Receptors, LHRH; C000731204:acoramidis; D019817:Benzoic Acid