The University Record, November 12, 1996

U-M chemist identifies compounds that block first step in lupus-related kidney damage

By Sally Pobojewski
News and Information Services

A U-M researcher has identified chemical compounds that lock onto antibodies produced by mice with the autoimmune disorder systemic lupus erythematosus (SLE) and prevent those antibodies from binding to DNA. Binding between lupus antibodies and DNA is the first step in a series of immunological reactions that can cause serious kidney damage and sometimes death in some individuals with lupus, according to Gary D. Glick, associate professor of chemistry.

The study by Glick; Jonathan A. Ellman, assistant professor of chemistry at the University of California at Berkeley; and their graduate students was published in the Oct. 30 issue of the Journal of the American Chemical Society.

The human body produces millions of protein molecules called antibodies, each customized to bind to one specific invading bacteria or virus and hold it prisoner until it is targeted for destruction by other immune system molecules. "Some individuals with lupus produce a unique type of antibody that sees their own DNA as the `invader,'" Glick explains.

In some lupus patients, these antibodies bind to sections of DNA and become lodged in the patient's kidneys, triggering inflammatory reactions which can lead to kidney failure. Researchers estimate there are more than 500,000 persons with lupus in the United States---90 percent of whom are women.

According to Glick, his study shows the promise of a potentially important new treatment strategy for lupus. This approach focuses on preventing molecular binding between antibodies and DNA---the first step in the process that triggers the inflammatory response---instead of using drugs to suppress the patient's entire immune system after the process is under way.

"Our research has focused on identifying the structural elements of antibodies and the chemical mechanisms these antibodies use in the DNA binding reaction," Glick says. "While there may be many different types of DNA-binding antibodies produced in lupus, previous work in my lab suggests most have similar structures at the DNA binding site and seem to use similar molecular mechanisms in the binding reaction. If we can block that binding site or even partially disable the linkage between the antibody and DNA, it may be possible to prevent kidney damage."

Glick's research also is significant because of the method he used to identify the molecules tested in his study. Using a new "chemical cloning" technique called combinatorial chemistry, which was pioneered by Ellman and others, Glick was able to quickly and easily create 1,680 derivatives of a class of low-molecular-weight organic compounds called 1,4-Benzodiazepines.

"We selected benzodiazepines, because they have chemical elements which are similar to DNA bases and in principle should compete with DNA for binding to anti-DNA antibodies," Glick explains. "But we had no idea whether or not they would bind with the antibodies. The beauty of combinatorial chemistry is that you don't have to understand the binding mechanism itself to come up with compounds that work. It's sort of like playing the lottery."

Of the 1,680 variations tested, Glick found several that were somewhat effective at blocking the antibody's binding site, with one proving more effective than the others. "While these initial compounds may not be drugs themselves, they are valuable leads that may help researchers find more effective anti-DNA inhibitors," Glick says.

While Glick used anti-DNA antibodies produced by mice with lupus in his experiments, he said antibodies produced by humans with lupus appear to be structurally similar. "There is a good chance that molecules that inhibit binding by mouse antibodies will be equally effective at inhibiting human proteins," he says.

Glick currently is testing his most effective compound in a small number of mice to determine whether it helps prevent or reduce lupus-related kidney damage in the animals. "Initial results are intriguing," he says, "but more studies will be needed before we know anything definite."

The research was funded by the National Institutes of Health. U-M graduate student Shawn Y. Stevens, former U-M graduate student Patrick C. Swanson, and University of California at Berkeley graduate students Barry A. Bunin and Matthew J. Plunkett contributed to the research project.