Handling flexible parts in RNA nanotechnology

As a road to advanced nanotechnology, RNA nanotechnology offers greater structural and functional versatility than does DNA nanotechnology. A disadvantage of multiple structural motifs, however, is that finding small molecules that bind specifically to an RNA molecule is more difficult than, for example, finding small molecules that bind specifically to protein molecules, which exhibit single defined structures. Because the last decade has also shown RNA to play a much broader role in cellular function in higher (meaning eukaryotic) organisms than was previously appreciated, this issue is receiving greater attention as researchers look for drugs that target specific RNA molecules. Designing interactions between RNA molecules and small molecules or nanoparticles could also be important for RNA nanotechnology. Researchers at the University of Michigan and the University of California, Irvine have now developed a new way to search for drugs that target RNA. Physorg.com points to this University of Michigan news release “Hitting moving RNA drug targets“:

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 [abstract].

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 encounters with drug molecules actually caused RNA’s shape changes, and that it was impossible to predict what shape an RNA would adopt upon binding to a given small molecule. However, in earlier research, Al-Hashimi’s team challenged this conventional “induced-fit” concept by showing that the RNA, on its own, can dance through the various shapes that it adopts when bound to different drugs. The team discovered that each drug molecule simply “waits” for the RNA to morph into its preferred shape and then latches onto it. …

The researchers validated their method by using it to discover six drug candidates to target an RNA molecule from HIV called TAR.

Further experiments showed that, for the six potential drug molecules, the method not only successfully predicted that they would bind to TAR, it also showed—with atomic-level accuracy—where on the RNA molecule each drug would bind. …

The eventual incorporation of both protein and RNA components into complex molecular machine systems will likely benefit from current drug discovery efforts aimed at both protein and RNA targets.

Leave a comment