Design of novel small molecule base-pair recognizers of toxic CUG RNA transcripts characteristics of DM1

Abstract

Graphical abstract

Development of Therapeutic Approaches for Myotonic Dystrophies Type 1 and Type 2

“…It has been suggested that the increased stability of the mutant CUG-containing mRNA might be due to binding of MBNL1 to the mutant CUG repeats. Therefore, many studies have been focused on the identification of small molecules and other approaches that might disrupt binding of MBNL1 to the mutant CUG repeats and might reduce the number of CUG foci, improving splicing of mRNAs, regulated by MBNL1 (reviewed in references [ 59 , 60 , 61 , 62 , 63 ]). These small molecules have been identified using the screening of the compound libraries or synthesized by special design.…”

“…Main criteria to evaluate the efficacy of the identified small molecules included prevention of MBNL1 binding to the expanded CUG repeats, reduction in CUG foci and correction of splicing targets, known to be misregulated in DM1 using cell culture lines from patients with DM1 or DM1 mice. Using these parameters, various small molecules correcting MBNL1 activity and improving splicing were identified and their number is growing fast [ 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 ]. The list of small molecules that improve MBNL1 activity includes anti-infective agents (such as pentamidine, furamidine and erythromycin) [ 64 , 65 , 66 ], compounds affecting microtubules [ 68 ] and small molecules increasing MBNL1 levels (such as the anti-autophagic drugs and inhibitors of HDAC) [ 67 , 71 ].…”

Transcriptome-Wide Studies of RNA-Targeted Small Molecules Provide a Simple and Selective r(CUG)exp Degrader in Myotonic Dystrophy

“…Despite the challenging nature of designing and discovering novel and selective RNA binders, ,, various strategies have been successfully implemented to afford bioactive molecules, including structure-based and sequence-based design methods. ,, For example, a small molecule with a mixed mode of action (dual-targeting DNA and RNA) was designed to bind 1 × 1 nucleotide U/U internal loops via a Janus-Wedge interaction informed by an X-ray crystal structure of short r­(CUG) repeats . A follow-up on this strategy was reported recently, and although the compounds modestly reduced the number of nuclear foci, they had no effect on alternative splicing defects . A biochemical assay that studied displacement of MBNL1 from r­(CUG) exp in vitro afforded small molecules with activity in cells.…”

“…84 A follow-up on this strategy was reported recently, and although the compounds modestly reduced the number of nuclear foci, they had no effect on alternative splicing defects. 85 A biochemical assay that studied displacement of MBNL1 from r(CUG) exp in vitro afforded small molecules with activity in cells. Of note, those studies identified small molecules that inhibited the r(CUG) exp -MBNL1 interaction by binding both the RNA and the protein.…”

Time-controlled and muscle-specific CRISPR/Cas9-mediated deletion of CTG-repeat expansion in the DMPK gene

“… 17 , 18 , 19 , 20 Both in vitro and in vivo models have been used to test therapeutic molecules, including antisense synthetic oligonucleotides or pharmacologic compounds such as small molecules or peptides that target the mutant transcripts. 21 , 22 , 23 , 24 , 25 , 26 Although successful in improving the phenotype in DM1 mouse models, these approaches require repeated administration of the therapeutic molecule, target only some aspects of the multisystemic disorder, and do not eliminate the disease-causing mutation. In addition, their application in DM1 patients has obtained scarce success so far.…”