A prototype drug created by researchers at the University of Illinois at Chicago shows promise in slowing replication of the virus responsible for severe acute respiratory syndrome, or SARS. Currently, there are no effective antiviral agents or vaccines for SARS, which killed almost 800 people in an epidemic in 2002-2003.
On the basis of their success, the researchers have received an $8 million grant from the National Institute of Allergy and Infectious Diseases to develop protease inhibitors that would block key enzymes in the SARS virus and hamper its advance. Protease inhibitors, a class of drugs capable of disrupting enzymes that digest proteins, have been successfully used to thwart the human immunodeficiency virus, which causes AIDS, a University release says.
"Data from SARS patients indicate that replication of the virus peaks 10 days after the onset of fever," Michael Johnson, the study's principal investigator said adding, "By administering protease inhibitors early, when feverish symptoms have started, the drugs could reduce the viral load and ameliorate the disease."
One of the first steps in that process is the production of a long chain of proteins, all of which are needed for the virus to propagate. Two enzymes, or proteases, clip the chain to release the individual proteins, the parts needed to assemble a mature virus. These two proteases -- called 3CLpro and PLpro -- are UIC's targets for drug therapy.
"If we can block 3CLpro and probably PLpro, then we can stop the SARS virus from replicating," Johnson said.
Under the grant, Andrew Mesecar, associate professor of pharmacy, will study details of the three-dimensional structure of the two enzymes using x-ray crystallography.
The detailed structures will reveal the precise locations and chemical properties of pockets where the enzymes bind the SARS virus's long protein chain.
Crucial to the endeavour is professor Arun Ghosh's strategy of targeting not the sidechains of the proteases, but their backbones. When viruses mutate, as they frequently do, thwarting the action of drugs, the mutations typically occur in these sidechains.
"By targeting the backbone, we create a drug that the virus probably will not be able to evade," Johnson said.
Susan Baker, a professor of microbiology and immunology at Loyola University Stritch School of Medicine who is collaborating in the research, will test the newly developed protease inhibitors to determine whether and how quickly they slow the enzymes' activity inside living cells.
The prototype drug developed earlier by Ghosh, an inhibitor of 3CLpro, was an improvement on a design published in the scientific literature. Shipped to the Centers for Disease Control and Prevention for testing on a live virus, the prototype proved to be 1,000 times more effective than the original compound in inhibiting 3CLpro.
However, Johnson, said, the prototype drug blocked several, but not all, of the enzyme's pockets. "The goal is to create compounds that will block all possible binding sites in the proteases to put them out of business."
Testing of the protease inhibitors on live viruses will be done at laboratories established by the National Institutes of Health.