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In situ growth of a stoichiometric PEG-like conjugate at a protein's N-terminus with significantly improved pharmacokinetics.

Publication ,  Journal Article
Gao, W; Liu, W; Mackay, JA; Zalutsky, MR; Toone, EJ; Chilkoti, A
Published in: Proc Natl Acad Sci U S A
September 8, 2009

The challenge in the synthesis of protein-polymer conjugates for biological applications is to synthesize a stoichiometric (typically 1:1) conjugate of the protein with a monodisperse polymer, with good retention of protein activity, significantly improved pharmacokinetics and increased bioavailability, and hence improved in vivo efficacy. Here we demonstrate, using myoglobin as an example, a general route to grow a PEG-like polymer, poly(oligo(ethylene glycol) methyl ether methacrylate) [poly(OEGMA)], with low polydispersity and high yield, solely from the N-terminus of the protein by in situ atom transfer radical polymerization (ATRP) under aqueous conditions, to yield a site-specific (N-terminal) and stoichiometric conjugate (1:1). Notably, the myoglobin-poly(OEGMA) conjugate [hydrodynamic radius (R(h)): 13 nm] showed a 41-fold increase in its blood exposure compared to the protein (R(h): 1.7 nm) after IV administration to mice, thereby demonstrating that comb polymers that present short oligo(ethylene glycol) side chains are a class of PEG-like polymers that can significantly improve the pharmacological properties of proteins. We believe that this approach to the synthesis of N-terminal protein conjugates of poly(OEGMA) may be applicable to a large subset of protein and peptide drugs, and thereby provide a general methodology for improvement of their pharmacological profiles.

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Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

September 8, 2009

Volume

106

Issue

36

Start / End Page

15231 / 15236

Location

United States

Related Subject Headings

  • Polyethylene Glycols
  • Myoglobin
  • Molecular Structure
  • Drug Discovery
  • Biopolymers
  • Biological Availability
  • Acrylates
 

Citation

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Gao, W., Liu, W., Mackay, J. A., Zalutsky, M. R., Toone, E. J., & Chilkoti, A. (2009). In situ growth of a stoichiometric PEG-like conjugate at a protein's N-terminus with significantly improved pharmacokinetics. Proc Natl Acad Sci U S A, 106(36), 15231–15236. https://doi.org/10.1073/pnas.0904378106
Gao, Weiping, Wenge Liu, J Andrew Mackay, Michael R. Zalutsky, Eric J. Toone, and Ashutosh Chilkoti. “In situ growth of a stoichiometric PEG-like conjugate at a protein's N-terminus with significantly improved pharmacokinetics.Proc Natl Acad Sci U S A 106, no. 36 (September 8, 2009): 15231–36. https://doi.org/10.1073/pnas.0904378106.
Gao W, Liu W, Mackay JA, Zalutsky MR, Toone EJ, Chilkoti A. In situ growth of a stoichiometric PEG-like conjugate at a protein's N-terminus with significantly improved pharmacokinetics. Proc Natl Acad Sci U S A. 2009 Sep 8;106(36):15231–6.
Gao, Weiping, et al. “In situ growth of a stoichiometric PEG-like conjugate at a protein's N-terminus with significantly improved pharmacokinetics.Proc Natl Acad Sci U S A, vol. 106, no. 36, Sept. 2009, pp. 15231–36. Pubmed, doi:10.1073/pnas.0904378106.
Gao W, Liu W, Mackay JA, Zalutsky MR, Toone EJ, Chilkoti A. In situ growth of a stoichiometric PEG-like conjugate at a protein's N-terminus with significantly improved pharmacokinetics. Proc Natl Acad Sci U S A. 2009 Sep 8;106(36):15231–15236.
Journal cover image

Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

September 8, 2009

Volume

106

Issue

36

Start / End Page

15231 / 15236

Location

United States

Related Subject Headings

  • Polyethylene Glycols
  • Myoglobin
  • Molecular Structure
  • Drug Discovery
  • Biopolymers
  • Biological Availability
  • Acrylates