Angew. Chem. Int. Ed. 52, 1462–1465 (2013)

The production of a faulty protein or of too much of a particular protein is the root cause of many diseases. A common approach to treatment is to attempt to modulate the effect of that protein, but an alternative would be to change how much is produced in the first place. This is the basis of ongoing research in small-interfering RNAs (siRNA) — short double-stranded RNA molecules that bind to messenger RNA and interfere with the translation process that results in protein production. Poor cellular permeability for siRNAs is a problem, however, and so Lirui Guan and Matthew Disney from the Scripps Research Institute in Florida are developing an alternative approach by designing small molecules that can bind to and induce cleavage of specific RNA sequences.

Myotonic dystrophy type 1 is a chronic disease that is caused by the presence of a repeating CUG base sequence in messenger RNA. This structure binds to and inactivates important proteins and ultimately results in the disease symptoms. The Disney research group has previously described a therapeutic strategy in which small molecules can bind to the CUG repeat unit and displace the proteins that would otherwise bind there. Their strategy (pictured) relies on the use of a peptoid backbone (black) to display two bis-benzimidazole binding units (Ht, blue) that are appended to the backbone through the use of copper(I)-catalysed Huisgen cycloadditions to form the triazoles (green). In this latest work they incorporate an N-hydroxypyridine-2(1H)-thione (red) — a structure known to generate hydroxyl radicals on photolysis — with the aim of not just binding to the problematic RNA structure, but cleaving it as well.

Using controls that omit the RNA binding group (Ht) and the radical generating unit, Guan and Disney then tested the effectiveness of their design. The addition of the radical-generating hydroxypyridone structure was found to slightly decrease the strength of binding to the RNA, but on photolysis the potency was increased approximately six-fold. The modular nature of this RNA-cleaving molecule should enable the rapid development of improved cleavage agents that can target a variety of RNA sequences.