This research explores a novel antisense molecular design concept for controlling binding cooperativity and selectivity in the development of bimodal nucleic acid probes that contain the right-handed helical domain for recognition of RNA targets and the left-handed self-complementary arms for inducing binding cooperativity. Such a molecular design, in principle, should permit precision control over the binding affinity, sequence-specificity, and selectivity, in favour of the expanded RNA-triplet repeats over the shorter (normal-length) counterparts. In addition to being more sequence-specific and selective in recognition, such a design should enable chemical modifications in the backbone as well as in the nucleobases with relative ease for improving the pharmacokinetic properties. We will present the latest data, demonstrating that such oligonucleotide molecules could be developed for targeting CAG-RNA repeats that are associated with Huntington’s disease. The design concept is general, and if successfully developed, could be applied to several other RNA-triplet repeats.

Controlling binding selectivity and cooperativity through directional Watson-Crick H-bonding

ACS Spring 2022

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