Seattle research to map disease with U.S. grant

It used to be that drugs were discovered largely by luck.

Ages ago, observant healers noticed the bark of a certain willow tree reduced fever and pain. Centuries later, scientists identified the chemical responsible and figured out how to manufacture aspirin.

In today's era of designer drugs, researchers start with a detailed understanding of a disease or disorder, then tailor remedies to match.

Now, Seattle scientists are joining this methodical search for cures in a big way.

With a $30.6 million federal grant, the Seattle Biomedical Research Institute (SBRI) will unravel the structures of thousands of toxins and other compounds produced by bacteria, viruses and parasites. The goal is to discover molecular Achilles' heels that can be exploited to design new drugs and vaccines.

The diseases that will be studied include influenza, drug-resistant tuberculosis, bacteria that cause ulcers and the drug-resistant strain of staphylococcus responsible for increasing numbers of skin infections. Some of the bugs, like the ones that cause cholera and typhus, are potential bioterror agents.

"We'll really be looking at things that haven't had huge amounts of resources thrown at them," said Peter Myler, head of the private lab's new Seattle Structural Genomics Center for Infectious Disease.

The effort won't yield drugs directly. But the results — which will be publicly available — will lay the groundwork for future drug development.

With an assembly-line approach, researchers will be able to process a hundred or more compounds at the same time, greatly speeding up the process and cutting the cost per compound.

"Our approach is not particularly different from other labs, but the scale is," Myler said.

The focus will be on key proteins produced by disease-causing microbes. For example, botulinum toxin — famed for smoothing wrinkles and causing food poisoning — is a neurotoxic protein produced by a bacterium. Other proteins allow viruses to slip inside cells, enable parasites to evade host immune systems, or help drug-resistant bugs shrug off the effects of antibiotics.

"Proteins are what do all the work in cells," Myler said. "Most traditional drugs target a particular protein and disrupt its activity in some way or another."

Protease inhibitors, the revolutionary class of drugs that has extended the lives of millions of HIV-infected people, work by interfering with a protein crucial for viral replication. Scientists had to understand that protein's structure before developing the treatment, said Lance Stewart, president of deCODE biostructures, part of the SBRI project.

The Bainbridge Island operation is a subsidiary of deCODE genetics, an Icelandic company that offers personal genome sequencing for $985 and is working on drugs based on genetic susceptibilities to diseases.

For the five-year SBRI project, scientists at deCODE will use an X-ray technique to analyze proteins down to the atomic level. The proteins themselves will be produced at SBRI's headquarters in South Lake Union.

"You get very high-resolution pictures," Stewart said. "Once you see what the structure of your target looks like, you can think about designing chemicals to interfere with or improve its activity."

A three-dimensional model of a protein can reveal folds or slots where a drug could attach, said Valentina DiFrancesco, who oversees the project for the National Institute of Allergy and Infectious Diseases (NIAID), a branch of the National Institutes of Health. The institute also funded a second, $30 million structural genomics center at Northwestern University.

Some scientists have questioned the value of a similar federal project to determine the structures of large numbers of proteins without regard to their function. The result, says an analysis published last year in the journal Science, is a lot of basic information — but not an impressive number of drug leads.

Since the NIAID project will focus exclusively on compounds known to be important in disease, it should yield more promising compounds for drug developers to follow up on, DiFrancesco said.

None of the toxic bugs will be grown in Seattle, Myler said. To mass-produce proteins, researchers need only the snippets of DNA, or genes, that code for the proteins.

Researchers from the University of Washington and Battelle Northwest in Richland also will participate in the project.

Sandi Doughton: 206-464-2491 or sdoughton@seattletimes.com