In Situ Growth of a Stoichiometric Peg-Like Conjugate at a Protein's N-terminus with Significantly Improved Pharmacokinetics

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 bioavailabil...

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Published inProceedings of the National Academy of Sciences - PNAS Vol. 106; no. 36; pp. 15231 - 15236
Main Authors Gao, Weiping, Liu, Wenge, Mackay, J. Andrew, Zalutsky, Michael R., Toone, Eric J., Chilkoti, Ashutosh, Demain, Arnold L.
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences 08.09.2009
National Acad Sciences
Subjects
Acrylates - chemistry
Aldehydes
Biological Availability
Biological Sciences
Biopolymers - biosynthesis
Biopolymers - pharmacokinetics
Blood
Drug Discovery - methods
Drugs
Elution
Glycols
Medical treatment
Molecular Structure
Myoglobin - chemistry
Peptides
Pharmacokinetics
Pharmacology
Phosphates
Physical Sciences
Polyethylene Glycols - chemistry
Polymerization
Polymers
Protein synthesis
Proteins
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Summary: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 (Rh): 13 nm] showed a 41-fold increase in its blood exposure compared to the protein (Rh: 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.
Bibliography:Author contributions: W.G. and A.C. designed research; W.G., W.L., and J.A.M. performed research; W.G., W.L., and J.A.M. analyzed data; and W.G., M.R.Z., E.J.T., and A.C. wrote the paper.
Edited by Arnold L. Demain, Drew University, Madison, NJ, and approved July 17, 2009
1Present address: Pharmacology and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA 90033.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0904378106