Small molecules that target the toxic RNA in myotonic dystrophy type 2

Area of Science:

• Molecular Biology
• Genetics
• Drug Discovery

Background:

• Myotonic Dystrophy type 2 (DM2) is a genetic disorder caused by expanded CCTG repeats in the ZNF9 gene.
• These repeats sequester the muscleblind-like protein 1 (MBNL1), disrupting its function as an alternative splicing regulator and causing disease.
• Current therapeutic strategies are limited.

Purpose of the Study:

• To identify and develop novel small molecules that disrupt the toxic interaction between MBNL1 and expanded CCUG repeats.
• To improve upon previous lead compounds by enhancing water solubility and cell permeability.
• To evaluate the efficacy of new ligands in disrupting MBNL1-r(CCUG)n interactions and cellular foci.

Main Methods:

• Design and synthesis of novel ligands incorporating a triaminopyrimidine recognition unit and a bisamidinium groove binder.
• In vitro inhibition assays to determine the potency of ligands against MBNL1-r(CCUG)8.
• Cell-based assays using a DM2 model to assess the disruption of MBNL1-r(CCUG)n foci.
• Cytotoxicity assays to evaluate the safety profile of the developed ligands.

Main Results:

• Optimized ligands demonstrated low micromolar inhibition potency against the MBNL1-r(CCUG)8 interaction.
• These novel compounds were the first to successfully disrupt MBNL1-r(CCUG)n foci in a DM2 cell culture model.
• The developed ligands exhibited low cytotoxicity, suggesting a favorable safety profile.

Conclusions:

• The newly developed bisamidinium groove binders are effective disruptors of the MBNL1-r(CCUG)n interaction.
• These ligands represent promising lead agents for the development of novel therapeutics for Myotonic Dystrophy type 2.
• Further investigation into these compounds could lead to effective treatments for DM2 patients.