Directed Polymerization Increases Potency of Protein-Based Drugs

Investigators from Duke University (Durham, NC, USA) were seeking a replacement for the currently used approach of chemically linking a protein drug to the polymer polyethylene glycol (PEG). This method only works with 10-20% efficiency, so that very expensive starting materials are wasted. Furthermore, the two large molecules are attached by a small chemical link and often these linkages can occur at many different sites on the protein; therefore, the final product is poorly defined and to some extent ineffective.

In the current study, the investigators used myoglobin as a model for a protein-based drug. They employed an atom transfer radical polymerization (ATRP) technique under aqueous conditions to grow a PEG-like polymer, poly(oligo(ethylene glycol) methyl ether methacrylate) [poly(OEGMA)], from the N-terminus of myoglobin's amino acid chain.

Results published in the August 25, 2009, online edition of the journal Proceedings of the [U.S.] National Academy of Sciences (PNAS) revealed that synthesis of the polymer was 70% more efficient than preparation of a myoglobin-polyethylene glycol compound. Following injection into mice, the new myoglobin polymer remained available in the blood stream 41-times longer than unmodified myoglobin.

"The dramatic improvement in how the new compound acted encourages us that this new approach will have broad applications in improving the efficacy of many protein drugs,” said senior author Dr. Ashutosh Chilkoti, professor of biomedical engineering at Duke University. "Because the compound is biodegradable, we should in principle be able to make even larger protein-polymer combinations with potentially even better pharmacologic properties. We also addressed the problem of getting a pure and well-defined product by growing the polymer from a single, unique site on the protein. Another twist to our work is that instead of using PEG, we used a somewhat different polymer that turns out to be as good, and perhaps even better than PEG in extending circulation of the protein in the body.”

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