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Rational design of bioactive, modularly assembled aminoglycosides targeting the RNA that causes myotonic dystrophy
Jessica L Childs-Disney1, Raman Parkesh, Masayuki Nakamori
1Department of Chemistry, Scripps Florida, 130 Scripps Way, Jupiter, FL 33458, USA.
Abstract:
Myotonic dystrophy type 1 (DM1) is caused when an expanded r(CUG) repeat (r(CUG)(exp)) binds the RNA splicing regulator muscleblind-like 1 protein (MBNL1) as well as other proteins. Previously, we reported that modularly assembled small molecules displaying a 6'-N-5-hexynoate kanamycin A RNA-binding module (K) on a peptoid backbone potently inhibit the binding of MBNL1 to r(CUG)(exp). However, these parent compounds are not appreciably active in cell-based models of DM1. The lack of potency was traced to suboptimal cellular permeability and localization. To improve these properties, second-generation compounds that are conjugated to a d-Arg(9) molecular transporter were synthesized. These modified compounds enter cells in higher concentrations than the parent compounds and are efficacious in cell-based DM1 model systems at low micromolar concentrations. In particular, they improve three defects that are the hallmarks of DM1: a translational defect due to nuclear retention of transcripts containing r(CUG)(exp); pre-mRNA splicing defects due to inactivation of MBNL1; and the formation of nuclear foci. The best compound in cell-based studies was tested in a mouse model of DM1. Modest improvement of pre-mRNA splicing defects was observed. These studies suggest that a modular assembly approach can afford bioactive compounds that target RNA.
Insights
New drug delivery strategies improve treatment for myotonic dystrophy type 1 (DM1). Researchers enhanced small molecules to better enter cells, effectively correcting DM1 cellular defects and showing promise in mouse models.
Area of Science:
- Biochemistry
- Molecular Biology
- Drug Discovery
Background:
- Myotonic dystrophy type 1 (DM1) is a genetic disorder caused by expanded RNA repeats that sequester RNA-binding proteins.
- Muscleblind-like 1 protein (MBNL1) is a key regulator of RNA splicing disrupted in DM1 by binding to expanded r(CUG) repeats.
Purpose of the Study:
- To develop second-generation small molecules with improved cellular permeability and localization for DM1 treatment.
- To evaluate the efficacy of these enhanced compounds in cell-based and animal models of DM1.
Main Methods:
- Synthesis of small molecules conjugated to a d-Arg(9) molecular transporter.
- Testing compound efficacy in cell-based DM1 models, assessing translational defects, splicing abnormalities, and nuclear foci formation.
- Evaluating the best compound in a DM1 mouse model.
Main Results:
- Second-generation compounds demonstrated significantly enhanced cellular uptake compared to parent molecules.
- Compounds were efficacious in cell-based DM1 models at low micromolar concentrations, correcting key disease hallmarks.
- Modest improvement in pre-mRNA splicing defects was observed in the DM1 mouse model.
Conclusions:
- Modular assembly of small molecules, enhanced with molecular transporters, can yield potent DM1 therapeutics.
- Improved cellular delivery is crucial for developing effective RNA-targeting drugs for genetic disorders like DM1.
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