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

Nat Chem. 2011 Dec 11;4(1):59-63. doi: 10.1038/nchem.1213.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Drug Stability
  • Models, Molecular
  • Molecular Structure
  • Polyethylene Glycols / chemistry*
  • Protein Binding
  • Proteins / chemistry*

Substances

  • Proteins
  • Polyethylene Glycols