500 giant steps in fight against disease

NORTHWESTERN (US) — Scientists have achieved a major milestone in the effort to wipe out some of the most lethal diseases on the planet.

Researchers have experimentally determined 500 three-dimensional protein structures from a number of bacterial and protozoan pathogens, which could potentially lead to new drugs, vaccines, and diagnostics to combat deadly infectious diseases.

“By determining the three-dimensional structure of these proteins, we can identify important pockets or clefts and design small molecules which will disrupt their disease-causing function,” says Peter Myler, affiliate professor of global health and medical education and biomedical informatics at the University of Washington who leads the Seattle Structural Genomics Center for Infectious Disease (SSGCID).

“Each solved structure provides an important piece of new knowledge for scientists about a wide variety of diseases.”

Recently, scientists provided structural data that offered insight into how specific differences in one of the RNA polymerase proteins in the swine flu virus changed the way it interacts with host cells, allowing it to infect humans.

This information could provide a basis for future antiviral agents that could be used to prevent replication of the flu virus.

Other structures solved come from little known or emerging pathogens that cause disease and death, but have been less well studied by the research community.

For example, the SSGCID solved the first protein structure from Rickettsia, bacterial pathogens carried by many ticks, fleas, and lice that causes several forms of typhus and spotted fever.

Scientists at the Center for Structural Genomics of Infectious Diseases (CSGID) determined the structure of a crucial enzyme in the shikimate pathway of Clostridium difficile, which is the most serious cause of antibiotic-associated diarrhea in humans and can lead to pseudomembranous colitis, a severe infection of the colon often resulting from eradication of the normal gut flora by antibiotics.

The shikimate pathway is essential for plants and bacteria like C. difficile, but is not present in animals, making this enzyme an attractive antibiotic target.

Researchers have also determined the structures of numerous proteins from other disease-causing organisms such as Bacillus anthracis (anthrax), Salmonella enterica (salmonellosis food poisoning), Vibrio cholerae (cholera), Yersinia pestis (plague), and Staphylococcus aureus (staph infections).

The CSGID is a consortium which includes researchers from Northwestern University, the University of Chicago, University College London, the University of Toronto, the University of Virginia, the University of Texas Southwestern Medical Center at Dallas, and the Washington University School of Medicine in St. Louis.

Mapping the structures of drug-resistant bacteria is also a priority for the two centers.

“Drug-resistant bacteria are an increasing threat to us and we need to get new drugs to stay ahead of them,” says Wayne Anderson, professor of molecular pharmacology and biological chemistry at Northwestern and principal investigator of CSGID.

“The recent years have brought not only an avalanche of new macromolecular structures, but also significant advances in the protein structure determination methodology that are now making their way into drug discovery. We provide the structural information so that in the future companies can develop new drugs to overcome resistance.”

The structures solved by the Centers are immediately made available to the international scientific community through the NIH-supported Protein Data Bank, providing a “blueprint” for development of new drugs, vaccines and diagnostics.

The Centers are on track to ultimately identify nearly 500 more structures by the end of the current five-year NIH contract in 2012. Apart from the protein structures, the two Centers make available to the scientific community all the clones and purified proteins that they produce in order to facilitate a global collaboration in the fight against deadly diseases.

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