The Johns Hopkins Gazette: June 9, 2003
June 9, 2003
VOL. 32, NO. 37


Drug Design Expert Sets Sights on SARS

Biologist to apply lessons learned from HIV studies to new respiratory disease

By Michael Purdy

Johns Hopkins Gazette Online Edition

Three days after the genome for the virus that causes SARS was released, biologists at Johns Hopkins identified a protein made by the virus that may provide a good target for drug development. Work is currently under way to produce the protein in recombinant form in sufficient amounts for drug design studies to begin.

The researchers found a protease, a protein essential to viral reproduction, encoded in the genome of the SARS virus, one of a class of viruses known as coronaviruses. Proteases usually act as a kind of scissors, cutting viral proteins into their active forms and enabling new viral particles to form and infect other cells. Several existing HIV treatments and other HIV treatments in development work by inhibiting the activity of HIV proteases.

"Not all viral proteases are the same. They have different structures and mechanisms of action," cautioned Ernesto Freire, the Henry Walters Professor of Biology in the Krieger School of Arts and Sciences. "It is necessary to characterize very precisely the SARS-associated coronavirus protease to validate its value as a drug development target.

"This basic characterization is necessary because the SARS-associated coronavirus protease belongs to a different family of proteases than the [proteases] from HIV, hepatitis C or herpes viruses, which have been vigorously studied and validated as targets for drug development," Freire noted.

Freire said he is delighted that he and other scientists are homing in on potential SARS vulnerabilities a mere six months after the disease first appeared in humans in the Guangdong province of China.

"It's been like a great detective novel, this race to find and stop the culprit behind this new disease," Freire said. "It's amazing how quickly we've made progress, from no one working on it two to three months ago, to having the bug identified and having its genome sequenced. This is the first epidemic of the 21st century, and the response from the public health community and the scientific community has been very good so far."

Freire has been working for several years to improve the way scientists design new drugs to treat HIV and other diseases. He advocates a combination of analytical approaches that, when applied to proteins essential to a pathogen, can reveal precise areas on the proteins that cannot genetically change without killing the microbes or destroying their ability to reproduce. With these areas identified, researchers can work to develop new drugs that bind to the critical areas, making it much more difficult for pathogens to develop resistance to the drugs.

Stephanie Leavitt, a graduate student in Freire's group, identified on April 17 a SARS protease encoded in the SARS genome, which had been compiled a few days earlier by several Canadian laboratories and was later published on May 1. Freire noted that it hasn't been conclusively shown that the protease Leavitt found is essential to SARS' survival. But scientists have found that inhibiting similar proteases can kill other coronaviruses.

Adrian Velazquez-Campoy, an associate research scientist in Freire's group, is working on the production of the recombinant protease.

Freire's group was recently awarded a supplement to its National Institutes of Health grant to allow the researchers to expand their work with HIV and drug development to SARS. They will take a closer look at the structural and thermodynamic properties of the protease, seeking the key areas that enable the protease to do its job. These areas may one day become targets for development of new drugs to stop SARS.