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

Authors

Sravan C. Penchala, University of the Pacific
Mark R. Miller, University of the Pacific
Arindom Pal, University of the Pacific
Jin Dong, University of the Pacific
Nikhil R. Madadi, University of the Pacific
Jinghang Xie, University of the Pacific
Hyun Joo, University of the PacificFollow
Jerry Tsai, University of the PacificFollow
Patrick Batoon, University of the Pacific
Vyacheslav V. Samoshin, University of the PacificFollow
Andreas H. Franz, University of the PacificFollow
Trevor Cox, University of the Pacific
Jesse Miles, University of the Pacific
William K. Chan, University of the PacificFollow
Miki S. Park, University of the PacificFollow
Mamoun M. Alhamadsheh, University of the PacificFollow

Document Type

Article

Publication Title

Nature Chemical Biology

Department

Chemistry

ISSN

1552-4450

Volume

11

Issue

10

DOI

10.1038/nchembio.1907

First Page

793

Last Page

798

Publication Date

9-7-2015

Abstract

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.

Recommended Citation

Penchala, S. C., Miller, M. R., Pal, A., Dong, J., Madadi, N. R., Xie, J., Joo, H., Tsai, J., Batoon, P., Samoshin, V. V., Franz, A. H., Cox, T., Miles, J., Chan, W. K., Park, M. S., & Alhamadsheh, M. M. (2015). A biomimetic approach for enhancing the in vivo half-life of peptides. Nature Chemical Biology, 11(10), 793–798. DOI: 10.1038/nchembio.1907
https://scholarlycommons.pacific.edu/cop-facarticles/117