The concept of orthogonality has been applied to many areas of chemistry, ranging from wave functions to chromatography. But it was Barany and Merrifield's orthogonal protecting group strategy that paved the way for solid phase peptide syntheses, other important classes of biomaterials such as oligosaccharides and oligonucleotides, and ultimately to a term in widespread usage that is focused on chemical reactivity and binding selectivity. The orthogonal protection strategy has been extended to the development of orthogonal activation, and recently the click reaction, for streamlining organic synthesis. The click reaction and its variants are considered orthogonal as the components react together in high yield and in the presence of many other functional groups. Likewise, supramolecular building blocks can also be orthogonal, thereby enabling programmed self-assembly, a superb strategy to create complex architectures. Overall, orthogonal reactions and supramolecular interactions have dramatically improved the syntheses, the preparation of functional materials, and the self-assembly of nanoscale structures.

A working hypothesis for the pathogenesis of myotonic dystrophy type 1 (DM1) involves the aberrant sequestration of an alternative splicing regulator, MBNL1, by expanded CUG repeats, r(CUG)^exp. It has been suggested that a reversal of the myotonia and potentially other symptoms of the DM1 disease can be achieved by inhibiting the toxic MBNL1-r(CUG)^exp interaction. Using rational design, we discovered an RNA-groove binding inhibitor (ligand 3) that contains two triaminotriazine units connected by a bisamidinium linker. Ligand 3 binds r(CUG)₁₂ with a low micromolar affinity (K_d = 8 ± 2 μM) and disrupts the MBNL1-r(CUG)₁₂ interaction in vitro (K_i = 8 ± 2 μM). In addition, ligand 3 is cell and nucleus permeable, exhibits negligible toxicity to mammalian cells, dissolves MBNL1-r(CUG)^exp ribonuclear foci, and restores misregulated splicing of IR and cTNT in a DM1 cell culture model. Importantly, suppression of r(CUG)^exp RNA-induced toxicity in a DM1 Drosophila model was observed after treatment with ligand 3. These results suggest ligand 3 as a lead for the treatment of DM1.

Myotonic dystrophy type 2 (DM2) is an incurable neuromuscular disease caused by expanded CCUG repeats that may exhibit toxicity by sequestering the splicing regulator MBNL1. A series of triaminotriazine- and triaminopyrimidine-based small molecules (ligands 1–3) were designed, synthesized and tested as inhibitors of the MBNL1–CCUG interaction. Despite the structural similarities of the triaminotriazine and triaminopyrimidine units, the triaminopyrimidine-based ligands bind with low micromolar affinity to CCUG repeats ( K_d ∼ 0.1–3.6 µM) whereas the triaminotriazine ligands do not bind CCUG repeats. Importantly, these simple and small triaminopyrimidine ligands exhibit both strong inhibition ( K_i ∼ 2 µM) of the MBNL1–CCUG interaction and high selectivity for CCUG repeats over other RNA targets. These experiments suggest these compounds are potential lead agents for the treatment of DM2.