Nav: Home

Novel polymer could improve protein-based drugs

August 19, 2009

DURHAM, N.C. - A new method for attaching a large protective polymer molecule to a protein appears to improve protein drugs significantly.

Bioengineers at Duke University developed the new approach and demonstrated in an animal model that the newly created protein-polymer combinations, known as conjugates, remained in circulation significantly longer than an unprotected protein.

The scientists say they are encouraged that their findings represent a new strategy to improve the efficacy of protein drugs.

Protein-based drugs are an increasingly important new class of drugs, said Ashutosh Chilkoti, Theo Pilkington Professor of Biomedical Engineering at Duke's Pratt School of Engineering. He cited such examples as insulin for the treatment of diabetes and more exotic "magic bullet" antibodies like herceptin that are used to treat certain cancers.

Unmodified proteins that are injected into the blood are quickly recognized by the body and broken down or cleared by the body's defense system, which limits their effectiveness as drugs. To get around this problem, drug makers have been attaching another molecule, a polymer known as polyethyleneglycol (PEG), to the protein in order to protect it. But this approach has its own drawbacks.

"The current method of combining the two molecules often only works with 10 to 20 percent efficiency, so that a lot of the very expensive starting materials are wasted," said Chilkoti, who had the results of his team's experiments published this week online in the Proceedings of the National Academy of Sciences. "Additionally, the two large molecules are attached by a small chemical link and often these linkages can occur at many different sites on the protein, so the final product is poorly defined."

Chilkoti took a different approach. Instead of combining two large molecules, he grew the polymer out from the protein itself, increasing the efficiency of the protein by more than 70 percent and greatly extending the amount of time it remained active in a living model.

"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," he said. "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."

There are many protein-polymer based medications in use today, such as human growth hormones, drugs to stimulate blood cell formation in cancer patients and anti-viral agents. Chilkoti will be reviewing existing protein-polymer drugs to determine if the new technique can improve their effectiveness.

In their experiments, the researchers used myoglobin, a protein responsible for creating the red pigments that give meat its color. Instead of creating a chemical bond between myoglobin and the polymer, the Duke researchers chose a specific spot on the protein, known as the N-terminus, and then grew the polymer from that specific location. Every protein has an N-terminus, so this method should be broadly useful, Chilkoti said.

After demonstrating they could create a stable compound using the new method, the researchers tested how well it worked by comparing its actions to the conventional compound in mice.

"The conventional compound - myoglobin - had a half-life of three minutes and was totally eliminated by two hours," Chilkoti explained. "By contrast, the new compound had a half-life 40 times greater and remained in circulation for 18 hours. The longer a protein remains in the system and is active, the more it helps the patient."

"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," Chilkoti said.

Another benefit of this approach, according to Chilkoti, is that the polymer should naturally degrade in the body over time and be easily excreted. "Because the compound is biodegradable, we should in principle be able to make even larger protein-polymer combinations with potentially even better pharmacologic properties," he said.

The researchers plan to apply their invention to other protein-based therapies, such as for cancer and diabetes, to determine if they can improve effectiveness of the protein drug while reducing its undesirable toxic effects.
-end-
Other Duke team members were Weiping Gao, Wenge Liu, J. Andrew Mackay, Michael Zalutsky and Eric Toone.

Duke University

Related Engineering Articles:

Engineering the meniscus
Damage to the meniscus is common, but there remains an unmet need for improved restorative therapies that can overcome poor healing in the avascular regions.
Artificially engineering the intestine
Short bowel syndrome is a debilitating condition with few treatment options, and these treatments have limited efficacy.
Reverse engineering the fireworks of life
An interdisciplinary team of Princeton researchers has successfully reverse engineered the components and sequence of events that lead to microtubule branching.
New method for engineering metabolic pathways
Two approaches provide a faster way to create enzymes and analyze their reactions, leading to the design of more complex molecules.
Engineering for high-speed devices
A research team from the University of Delaware has developed cutting-edge technology for photonics devices that could enable faster communications between phones and computers.
More Engineering News and Engineering Current Events

Best Science Podcasts 2019

We have hand picked the best science podcasts for 2019. Sit back and enjoy new science podcasts updated daily from your favorite science news services and scientists.
Now Playing: TED Radio Hour

Rethinking Anger
Anger is universal and complex: it can be quiet, festering, justified, vengeful, and destructive. This hour, TED speakers explore the many sides of anger, why we need it, and who's allowed to feel it. Guests include psychologists Ryan Martin and Russell Kolts, writer Soraya Chemaly, former talk radio host Lisa Fritsch, and business professor Dan Moshavi.
Now Playing: Science for the People

#537 Science Journalism, Hold the Hype
Everyone's seen a piece of science getting over-exaggerated in the media. Most people would be quick to blame journalists and big media for getting in wrong. In many cases, you'd be right. But there's other sources of hype in science journalism. and one of them can be found in the humble, and little-known press release. We're talking with Chris Chambers about doing science about science journalism, and where the hype creeps in. Related links: The association between exaggeration in health related science news and academic press releases: retrospective observational study Claims of causality in health news: a randomised trial This...