The prospect of using RNA as a drug target is of great interest to scientists, but due to its complex structure, designing ligands that bind to it is challenging. Scientists from the University of North Carolina at Chapel Hill, US, have overcome these difficulties by combining two weak ligands to make an RNA-binding conjugate that is far better than the sum of its parts.

Combining two RNA-binding ligands gives a conjugate that binds both single and double stranded regions of RNA

'Although cooperative binding has been explored in the past,' says Marcey Waters, who carried out the research with Lauren Cline, 'our system is the first example of coupling a sequence-selective threading intercalator with a -hairpin peptide that is known to selectively bind unpaired bases.' The result is a system that simultaneously targets both the single- and double-stranded regions of RNA. While the intercalator threads between two G-C base pairs adjacent to bulges in the RNA, the peptide targets exposed bases in the RNA's single-stranded loops and bulges, resulting in binding that is at least 30 times more favourable than for either unit alone. 

Yitzhak Tor, who investigates RNA-small molecule interactions at the University of California, San Diego, US, says that Waters' results are an important step forward. 'Increasing the affinity and selectivity of designer ligands to RNA is challenging and this work elegantly demonstrates the advantage of combining two distinct recognition modes.' He suggests that similar combined ligand systems could ultimately be useful if they are applied to RNA sequences that are validated as therapeutic targets.

Waters agrees that targeting medicinally relevant RNA structures is an important future goal in this area. 'The ability to develop high affinity, high selectivity ligands would open up RNA as a feasible drug target for the treatment of many types of disease, such as HIV,' she says.

Bailey Fallon

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