UW biochemists developing the next generation of virus fighters

Viruses such as influenza and chicken pox have existed throughout human history, but their ability to wreak devastation on a large scale is a relatively recent phenomenon.

As population density increased after the invention of agriculture, diseases could be communicated more easily across broad populations before humans developed resistance. While millennia have passed, the basic problem of disease hasn’t changed: it still takes time to develop resistance to emerging threats like SARS. And time, explains Trisha Davis, UW professor and acting chair of the Department of Biochemistry, is at a premium in a world that grows ever more crowded.

“Viruses are emerging — like SARS — that we don’t have resistance to,” says Davis. “They could have a devastating effect, unless we find ways to develop therapeutics quickly, in months rather than years.”

The answer to developing a quick fix for a virus? (Or the answers to a whole host of other medical issues?) It might be found in proteins. Diseases result from protein malfunctions. Therefore, figured David Baker, UW professor in the Department of Biochemistry and a Howard Hughes Medical Institute Investigator, adapting or designing proteins could be the key to preventing and curing disease.

This idea has led to the creation of the University of Washington’s Institute for Protein Design (IPD)—a new endeavor with the potential to revolutionize medicine and other fields. “Simply looking at the range of things that proteins do in living systems gives you a hint of what proteins could do if you designed them to order,” says Baker, a pioneer of protein design and the IPD’s director. “So the prospect of being able to design new proteins to solve 21st-century health problems is very exciting.”

“A lot of strides have been made lately with this new field,” says Michelle Scalley-Kim, Ph.D, ’03, director of research and strategy for the IPD. “These are built on an understanding of how a protein folds into its unique structure—whether it’s catalyzing a reaction or communicating between cells.” Much of that understanding has come from Baker’s work with a computer program called Rosetta, which analyzes proteins’ structures based on their amino acid sequences.

We want to design synthetic proteins that have exquisite specificity and are cheaper to produce.

Michelle Scalley-Kim, IPD director of research and strategy

One of the premises behind the medical use of designed proteins, says Davis, is that bigger is better. When researchers design drugs to combat disease, they are designing molecular structures that bind with the body’s proteins. When it comes to therapeutics, proteins have an advantage over small molecules—proteins are bigger, have more sites where they can bind with malfunctioning proteins, and contain more information than small molecules— which gives them tremendous potential.

“Big pharma has invested a lot of money into small-molecule discovery—things like aspirin,” Scalley-Kim explains. “But small molecules are not very specific, so you can’t treat all the disease you want to treat. We want to design synthetic proteins that have exquisite specificity and are cheaper to produce.”

The IPD already has made a significant step forward: the development of a novel protein that binds to the flu virus and blocks it from infecting cells. This protein has been licensed by a large pharmaceutical company for translation into a therapy to treat flu infections. Davis calls this work “stunning,” saying, “they’ve basically developed the proof of principle” for the use of protein design for therapeutics.

The IPD recently received federal funding in the form of a three-year grant from the Defense Threat Reduction Agency. In collaboration with researchers from UW’s Applied Physics Lab, IPD investigators will work to shorten the timeframe for developing proteins, similar to the flu-inhibitors, as countermeasures to bio-warfare infections.

Baker’s group is also exploring protein design for disease diagnostics. Currently, diseases are diagnosed using antibodies designed to respond to specific viruses and biomarkers in the body. Because designed proteins are more stable and cheaper to produce than antibodies, they could be ideal for use in developing countries.

“At some stage, [Seattle] will be a huge breeding ground for small companies who will take these therapeutics to market,” Davis predicts. “The institute has tremendous potential to enhance the local economy. I have no doubt that, with resources, great things for modern medicine will come out of the IPD. There’s a tremendous possibility to do good and help humankind.”