Defined D-hexapeptides bind CUG repeats and rescue phenotypes of myotonic dystrophy myotubes in a Drosophila model of the disease
Author
Rapisarda, Anna
Bargiela, Ariadna
Llamusi, Beatriz
Pont, Isabel
Estrada Tejedor, Roger
Garcia-España, Enrique
Artero, Ruben
Perez-Alonso, Manuel
Other authors
Universitat Ramon Llull. IQS
Publication date
2021-09-30ISSN
2045-2322
Abstract
In Myotonic Dystrophy type 1 (DM1), a non-coding CTG repeats rare expansion disease; toxic double-stranded RNA hairpins sequester the RNA-binding proteins Muscleblind-like 1 and 2 (MBNL1 and 2) and trigger other DM1-related pathogenesis pathway defects. In this paper, we characterize four D-amino acid hexapeptides identified together with abp1, a peptide previously shown to stabilize CUG RNA in its single-stranded conformation. With the generalized sequence cpy(a/t)(q/w)e, these related peptides improved three MBNL-regulated exon inclusions in DM1-derived cells. Subsequent experiments showed that these compounds generally increased the relative expression of MBNL1 and its nuclear-cytoplasmic distribution, reduced hyperactivated autophagy, and increased the percentage of differentiated (Desmin-positive) cells in vitro. All peptides rescued atrophy of indirect flight muscles in a Drosophila model of the disease, and partially rescued muscle function according to climbing and flight tests. Investigation of their mechanism of action supports that all four compounds can bind to CUG repeats with slightly different association constant, but binding did not strongly influence the secondary structure of the toxic RNA in contrast to abp1. Finally, molecular modeling suggests a detailed view of the interactions of peptide-CUG RNA complexes useful in the chemical optimization of compounds.
Document Type
Article
Document version
Published version
Language
English
Subject (CDU)
616.7 - Pathology of the organs of locomotion. Skeletal and locomotor systems
Keywords
Miotonia atròfica
Pages
15 p.
Publisher
Nature Portfolio
Is part of
Scientific Reports
Grant agreement number
info:eu-repo/grantAgreement/ISCIII i FEDER/PN I+D/PI13/00386
This item appears in the following Collection(s)
Rights
© L'autor/a
Except where otherwise noted, this item's license is described as http://creativecommons.org/licenses/by/4.0/