Childs-Disney, JL, Parkesh, R, Nakamori, M, Thornton, CA and Disney, MD. Rational design of bioactive, modularly assembled aminoglycosides targeting the RNA that causes myotonic dystrophy type 1. ACS Chem Biol 7: 1984-1993

Department of Chemistry, Scripps Florida , 130 Scripps Way, Jupiter, Florida 33458, United States.
ACS Chemical Biology (Impact Factor: 5.33). 11/2012; 7(12). DOI: 10.1021/cb3001606
Source: PubMed


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.

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    • "Finally, phase I and II clinical trials of a gapmer targeting mutant DMPK mRNA has been recently initiated (Isis Pharmaceuticals, 2014). A number of small-molecule probes have also been developed for targeting r(CUG) exp that displace MBNL1 and improve downstream defects (Arambula et al., 2009; Childs-Disney et al., 2012a, 2012b, 2013; Hoskins et al., 2014; Jahromi et al., 2013a, 2013b; Parkesh et al., 2012). These compounds were either identified from screening, designed from the structure of r(CUG) repeats, or designed from privileged RNA motif-small molecule interactions including modularly assembled compounds thereof. "
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