Poly(zwitterionic)protein conjugates offer increased stability without sacrificing binding affinity or bioactivity

• Published in: Nature chemistry 2011-12, Vol.4 (1), p.59-63
• Main Authors: Keefe, Andrew J., Jiang, Shaoyi
• Format: Article
• Language: English
• Subjects: 639/638/309; 639/638/455/954; Analytical Chemistry; Bioavailability; Biochemistry; Biological activity; Chemistry; Chemistry and Materials Science; Chemistry/Food Science; Drug Stability; Enzymes; Inorganic Chemistry; Models, Molecular; Molecular Structure; Molecular weight; Organic Chemistry; Physical Chemistry; Physiology; Polyethylene Glycols - chemistry; Polymers; Protein Binding; Proteins; Proteins - chemistry; Temperature
• ISSN: 1755-4330; 1755-4349
• DOI: 10.1038/nchem.1213

Treatment with therapeutic proteins is an attractive approach to targeting a number of challenging diseases. Unfortunately, the native proteins themselves are often unstable in physiological conditions, reducing bioavailability and therefore increasing the dose that is required. Conjugation with poly(ethylene glycol) (PEG) is often used to increase stability, but this has a detrimental effect on bioactivity. Here, we introduce conjugation with zwitterionic polymers such as poly(carboxybetaine). We show that poly(carboxybetaine) conjugation improves stability in a manner similar to PEGylation, but that the new conjugates retain or even improve the binding affinity as a result of enhanced protein–substrate hydrophobic interactions. This chemistry opens a new avenue for the development of protein therapeutics by avoiding the need to compromise between stability and affinity. Poly(ethylene glycol) conjugates have been widely used to improve the stability of proteins for use as therapeutics, but this stability comes at the expense of binding affinity. Here, poly(carboxybetaine) — a zwitterionic polymer — is shown to provide increased stability while also enhancing binding due to its super-hydrophilic nature.