Genetically Encoded Cholesterol-Modified Polypeptides

• Published in: Journal of the American Chemical Society Vol. 141; no. 2; pp. 945 - 951
• Main Authors: Mozhdehi, Davoud, Luginbuhl, Kelli M, Dzuricky, Michael, Costa, Simone A, Xiong, Sinan, Huang, Fred C, Lewis, Mae M, Zelenetz, Stephanie R, Colby, Christian D, Chilkoti, Ashutosh
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 16.01.2019
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/jacs.8b10687

Biological systems use post-translational modifications (PTMs) to control the structure, location, and function of proteins after expression. Despite the ubiquity of PTMs in biology, their use to create genetically encoded recombinant biomaterials is limited. We have utilized a natural lipidation PTM (hedgehog-mediated cholesterol modification of proteins) to create a class of hybrid biomaterials called cholesterol-modified polypeptides (CHaMPs) that exhibit programmable self-assembly at the nanoscale. To demonstrate the biomedical utility of CHaMPs, we used this approach to append cholesterol to biologically active peptide exendin-4 that is an approved drug for the treatment of type II diabetes. The exendin-cholesterol conjugate self-assembled into micelles, and these micelles activate the glucagon-like peptide-1 receptor with a potency comparable to that of current gold standard treatments.