Devising a nifty variation on a tested method to bind compounds useful in biological and medical research, a group of chemists at the University of Illinois at Chicago has discovered a new way to make permanent these bindings called ligation reactions.
The group, led by David Crich, distinguished professor of chemistry at UIC, reports their findings in the March 1 issue of the Journal of the American Chemical Society.
Crich, graduate student Venkataramanan Krishnamurthy and post-doctoral researcher Thomas Hutton modified a common reaction called a disulfide ligation, used to bridge the amino acid cysteine with a related sulfur-containing compound called a thiol.
"It's done in water and at room temperature and is widely applied by biochemists to conjugate all kinds of molecules onto proteins to make haptens for antibody generation," said Crich. "It has many applications."
But the disulfide ligation is not permanent, said Crich, which limits its usefulness in developing new medicines.
Crich's goal is to devise a room-temperature, water-based method to do protein glycosylation -- basically the process of hanging carbohydrate groups onto proteins.
"Glycosylated proteins are enormously important in immunology, as markers for cancer, and even as potential cancer vaccines," he said.
Crich's lab is good at performing glycosylation reactions, but needed to find a process for doing it in aqueous solutions and at room temperature. His group found a clue looking back at a reaction first described in the 1960s, in which compounds called allylic disulfides were rearranged to form a permanent linkage by removing one atom of sulfur.
But that chemistry, developed by Jack Baldwin, then at MIT and now at Oxford University, required many hours of heating at temperatures around 80 degrees Celsius.
"Our intention was to modify this chemistry to make it run at room temperature," said Crich. "What we decided to do was to replace one of the sulfur atoms in allylic disulfide with a selenium atom."
Crich's laboratory created an allylic selenosulfide that proved to work well at room temperatures in aqueous solutions, and provide a permanent ligation.
Crich modestly calls this work "the easy bit," adding that protein glycosylation is the real challenge ahead.
"That's important for drug delivery, particularly with long-acting drugs," he said. "There's a multitude of potential applications in combinatorial chemistry."
Funding for the research came from a larger grant for anthrax research awarded by the National Institutes of Health to Crich and other UIC researchers. The grant's principal investigator is Michael Johnson, professor and director of UIC's Center for Pharmaceutical Biotechnology.
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