New Class of Drugs to Block SARS Being Developed at UIC November 13, 2008
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Sam Hostettler | samhos@uic.edu |
Coronaviruses, which produce upper respiratory tract infections from SARS to childhood croup, depend on an enzyme called a protease (pro-tee-ace) to replicate and spread. The "papain-like protease" in the SARS virus also helps the virus evade the human immune system.
Using state-of-the-art robotics systems, a research team led by Andrew Mesecar, UIC professor of pharmaceutical biotechnology, screened a "library" of more than 50,000 diverse compounds for candidates that might inhibit the protease. Only two were identified that contained the properties researchers believed could become drugs, Mesecar said.
Collaborating with synthetic chemist Arun Ghosh of Purdue University, who invented the HIV protease drug darunavir that entered the market in 2007, the researchers tweaked the chemical structure of the two candidate compounds and "increased the potency of our original lead by almost two orders of magnitude," Mesecar said.
"The compounds block SARS virus replication in cells without any noticeable toxicity, indicating that this class of compounds could have a significant role in warding off SARS," he said.
Ghosh specializes in the structure-based design and sought to optimize interactions at the enzyme's active site to improve the drug properties of Mesecar's inhibitor leads.
"The design of this inhibitor was a challenge because we did not know the structure of the compound bound to the enzyme, which shows us how an inhibitor works and what parts need to be amplified or changed," Ghosh said.
Mesecar's doctoral student Kiira Ratia provided a breakthrough when she used X-ray crystallography to capture the structure of the inhibitor molecule bound to the protein. The structure confirmed that the inhibitor would be a good candidate for drug development because it showed that the inhibitor did not bond too strongly to the protein, Ghosh said, which can lead to toxicity.
SARS was first reported in Asia in February 2003. Over the next several months, the illness spread to more than 29 countries in North and South America, Europe and Asia before it was contained. It begins with a high fever, headache and body aches. About 10 percent to 20 percent of patients suffer diarrhea, and after two to seven days, a dry cough may develop. Most patients develop pneumonia. The infection spreads by close personal contact, often through coughing or sneezing.
According to the World Health Organization, 8,098 people worldwide were diagnosed with SARS during the 2003 outbreak; 774 died. There were 29 cases reported in the United States, but no fatalities.
"The development of novel antivirals against SARS is an important safeguard against future outbreaks and pandemics, but so far potent antivirals with efficacy in animal models have yet to be developed," Mesecar said.
The study has been published in the on-line version of the journal Proceedings of the National Academy of Sciences. Other authors include Scott Pegan, a UIC post-doctoral researcher in medicinal chemistry and pharmacognosy; Michael E. Johnson, professor and director of the UIC Center for Pharmaceutical Biotechnology; Bellur Prabhakar, UIC professor and head of microbiology and immunology; and Susan Baker of Loyola University Chicago Stritch School of Medicine.
The research is being funded by the National Institutes of Health. For more information about UIC, visit www.uic.edu.
Extended remarks as podcast audio file available