ANN ARBOR, Mich.---By accounting for the floppy, fickle nature of RNA, researchers at the University of Michigan and the University of California, Irvine have developed a new way to search for drugs that target this important molecule. Their work appears in the June 26 issue of Nature Chemical Biology.
Once thought to be a passive carrier of genetic information, RNA now is understood to perform a number of other vital roles in the cell, and its malfunction can lead to disease. The versatile molecule also is essential to retroviruses such as HIV, which have no DNA and instead rely on RNA to both transport and execute genetic instructions for everything the virus needs to invade and hijack its host. As more and more links to disease are discovered, the quest for drugs that target RNA is intensifying.
Searching for such drugs is not a simple matter, however. Most of today's drug-hunting tools are designed to find small molecules that bind to protein targets, but RNA is not a protein, and it differs from proteins in many key features. "So there's a growing need for high-throughput technologies that can identify compounds that bind RNA," said Hashim M. Al-Hashimi, the Robert L. Kuczkowski Professor of Chemistry and Professor of Biophysics at U-M.
Al-Hashimi and coworkers adapted an existing computational technique for virtually screening libraries of small molecules to determine their RNA-binding abilities. In this approach, the shape of a target molecule is first determined by X-ray crystallography or NMR spectroscopy; next, researchers run computer simulations to compute how well various small molecules---potential drugs, for example---nestle into and bind to the target structure. RNA presents a major challenge to this methodology because it doesn't have just one configuration; it's a floppy molecule, and depending on which small molecule it binds, it can assume vastly different shapes.
It once was thought that encounter
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University of Michigan