Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 108, Issue 29, Pages 11866-11871Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1018213108
Keywords
disease model; drug discovery; non-coding RNA disease; medicinal chemistry; RNA secondary structure
Categories
Funding
- Ministerio de Educacion y Ciencia
- Muscular Dystrophy Association
- Acciones de Articulacion, Generalitat Valenciana (GV) [IIARC02004-A-51, ACOMP2009-011]
- Ministerio de Ciencia e Innovacion (MICINN) [BFU2009-10940, BIO2007-60066]
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Myotonic dystrophy type 1 (DM1) is caused by the expansion of noncoding CTG repeats in the dystrophia myotonica-protein kinase gene. Mutant transcripts form CUG hairpins that sequester RNA-binding factors into nuclear foci, including Muscleblind-like-1 protein (MBNL1), which regulate alternative splicing and gene expression. To identify molecules that target toxic CUG transcripts in vivo, we performed a positional scanning combinatorial peptide library screen using a Drosophila model of DM1. The screen identified a D-amino acid hexapeptide (ABP1) that reduced CUG foci formation and suppressed CUG-induced lethality and muscle degeneration when administered orally. Transgenic expression of natural, L-amino acid ABP1 analogues reduced CUG-induced toxicity in fly eyes and muscles. Furthermore, ABP1 reversed muscle histopathology and splicing misregulation of MBNL1 targets in DM1 model mice. In vitro, ABP1 bound to CUG hairpins and induced a switch to a single-stranded conformation. Our findings demonstrate that ABP1 shows antimyotonic dystrophy activity by targeting the core of CUG toxicity.
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