May 17 2004
University of Chicago
scientists have identified a compound that halts the activity of a deadly toxin called anthrax lethal factor in laboratory tests. Nature Biotechnology will publish the findings online on May 16 and in the June issue of the journal's print edition.
Anthrax lethal factor can only be effectively treated with antibiotics if administered soon after infection, making it difficult to treat patients who were unknowingly exposed to the bacterium. The Chicago research aims to develop a drug that could treat anthrax after antibiotics become ineffective.
The Chicago team discovered that a compound called DS-998 showed promising activity against anthrax lethal factor in cell cultures. Lethal factor is a molecule that chops up and renders inactive a protein that helps cells stay healthy. DS-998 blocks lethal factor's harmful cutting action.
The Chicago research is also the first time application of mass spectrometry to screen a library of compounds for medical applications. "We screened 10,000 compounds in three days. We estimate that it would be possible to screen 50,000 compounds a day with available robotic equipment," said Milan Mrksich, Professor in Chemistry at the University of Chicago. His co-authors of the Nature Biotechnology article are Dal-Hee Min, a Ph.D. student in chemistry, and Wei-Jen Tang, Associate Professor in the Ben May Institute for Cancer Research, both at the University of Chicago,
Rapid screening is an important component in making drug development more economical. It can cost a pharmaceutical company $250 million to develop a drug. Research and development alone can exceed $25 million, Mrksich said. "Typically hundreds of thousands of molecules are screened to identify 10 that are candidate drug leads," he said.
The search focused on small-molecule compounds. "In order to prevent the action of these toxins you need to have a molecule that is easily penetrable into the cell," Tang said.
The DS-998 compound could one day lead to the development of a new drug for the treatment of anthrax, Tang said, but he cautioned that research remains in the early stages. Mrksich agreed. "Discovering proteins that have roles in diseases processes is the first step in the drug discovery process, but still a very long way from the actual development of a drug," Mrksich said.
Mass spectrometry is widely used to identify proteins in biological studies, but until now the technique has required specialized training. Mrksich and Min developed a way to allow mass spectrometry to be used as a routine tool in drug development by users from a broader range of scientific disciplines.
Although no faster than commonly used fluorescent assays, mass spectrometry is more accurate, according to the Chicago researchers. Fluorescent assays can alter the activity of the molecules they are trying to assess as well as produce false-positive results, Mrksich said.
The mass spectrometry technique has great potential for application to university research programs, which originate many drug targets, Mrksich said. "By having the screening facility on campus, it's possible to see basic research take one important step further toward a drug discovery development program," Mrksich said.
It was Min, the Ph.D. student, who recognized that a mass spectrometry method used in Mrksich's laboratory could be beneficially applied to drug screening. Min's work is supported by the University's Burroughs-Wellcome program that fosters graduate training at the intersection between the physical and biological sciences. Further support for the chemical screening project came from the National Science Foundation and the Ludwig Fund for Cancer Research. http://www.uchicago.edu/