Defined d-hexapeptides bind CUG repeats and rescue phenotypes of myotonic dystrophy myotubes in a Drosophila model of the disease

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...

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Autores principales:	Anna Rapisarda, Ariadna Bargiela, Beatriz Llamusi, Isabel Pont, Roger Estrada-Tejedor, Enrique Garcia-España, Ruben Artero, Manuel Perez-Alonso
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/0dbedd9c52a24137b9ee035f7dd3ec6c
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spelling	oai:doaj.org-article:0dbedd9c52a24137b9ee035f7dd3ec6c2021-12-02T17:37:40ZDefined d-hexapeptides bind CUG repeats and rescue phenotypes of myotonic dystrophy myotubes in a Drosophila model of the disease10.1038/s41598-021-98866-02045-2322https://doaj.org/article/0dbedd9c52a24137b9ee035f7dd3ec6c2021-09-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-98866-0https://doaj.org/toc/2045-2322Abstract 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.Anna RapisardaAriadna BargielaBeatriz LlamusiIsabel PontRoger Estrada-TejedorEnrique Garcia-EspañaRuben ArteroManuel Perez-AlonsoNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-15 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Anna Rapisarda Ariadna Bargiela Beatriz Llamusi Isabel Pont Roger Estrada-Tejedor Enrique Garcia-España Ruben Artero Manuel Perez-Alonso Defined d-hexapeptides bind CUG repeats and rescue phenotypes of myotonic dystrophy myotubes in a Drosophila model of the disease
description	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.
format	article
author	Anna Rapisarda Ariadna Bargiela Beatriz Llamusi Isabel Pont Roger Estrada-Tejedor Enrique Garcia-España Ruben Artero Manuel Perez-Alonso
author_facet	Anna Rapisarda Ariadna Bargiela Beatriz Llamusi Isabel Pont Roger Estrada-Tejedor Enrique Garcia-España Ruben Artero Manuel Perez-Alonso
author_sort	Anna Rapisarda
title	Defined d-hexapeptides bind CUG repeats and rescue phenotypes of myotonic dystrophy myotubes in a Drosophila model of the disease
title_short	Defined d-hexapeptides bind CUG repeats and rescue phenotypes of myotonic dystrophy myotubes in a Drosophila model of the disease
title_full	Defined d-hexapeptides bind CUG repeats and rescue phenotypes of myotonic dystrophy myotubes in a Drosophila model of the disease
title_fullStr	Defined d-hexapeptides bind CUG repeats and rescue phenotypes of myotonic dystrophy myotubes in a Drosophila model of the disease
title_full_unstemmed	Defined d-hexapeptides bind CUG repeats and rescue phenotypes of myotonic dystrophy myotubes in a Drosophila model of the disease
title_sort	defined d-hexapeptides bind cug repeats and rescue phenotypes of myotonic dystrophy myotubes in a drosophila model of the disease
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/0dbedd9c52a24137b9ee035f7dd3ec6c
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Defined d-hexapeptides bind CUG repeats and rescue phenotypes of myotonic dystrophy myotubes in a Drosophila model of the disease

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