Local RNA flexibility perturbation of the IRES element induced by a novel ligand inhibits viral RNA translation

RNA Biology
Gloria LozanoEncarnación Martínez-Salas

Abstract

The internal ribosome entry site (IRES) element located at the 5'untranslated genomic region of various RNA viruses mediates cap-independent initiation of translation. Picornavirus IRES activity is highly dependent on both its structural organization and its interaction with host factors. Small molecules able to interfere with RNA function are valuable candidates for antiviral agents. Here we show that a small molecule based on benzimidazole (IRAB) inhibited foot-and-mouth disease virus (FMDV) IRES-dependent protein synthesis in cells transfected with infectious RNA leading to a decrease of the virus titer, which was higher than that induced by a structurally related benzimidazole derivative. Interestingly, IRAB preferentially inhibited IRES-dependent translation in cell free systems in a dose-dependent manner. RNA structural analysis by SHAPE demonstrated an increased local flexibility of the IRES structure upon incubation with IRAB, which affected 3 stem-loops (SL) of domain 3. Fluorescence binding assays conducted with individual aminopurine-labeled oligoribonucleotides indicated that the SL3A binds IRAB (EC50 18 μM). Taken together, the results derived from SHAPE reactivity and fluorescence binding assays suggested that the...Continue Reading

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Citations

Jan 19, 2016·Journal of Molecular Biology·Gloria LozanoEncarnacion Martinez-Salas
Apr 8, 2016·Scientific Reports·Javier Fernandez-ChamorroEncarnacion Martinez-Salas
Jun 17, 2016·Bioinformatics·Juan Antonio Garcia-MartinPeter Clote
Jun 2, 2020·RNA Biology·Rosario Francisco-VelillaEncarnacion Martinez-Salas
Oct 9, 2019·Journal of Zhejiang University. Science. B·Gui-Zhen ZhengZhi-Yong Liu
Feb 10, 2017·Nucleic Acids Research·Rosa Diaz-ToledanoEncarnacion Martinez-Salas
Jan 23, 2018·Frontiers in Microbiology·Encarnacion Martinez-SalasAzman M Embarek
Dec 16, 2020·Nucleosides, Nucleotides & Nucleic Acids·Sergio Israel Rangel-GuerreroLuis Marat Alvarez-Salas

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Methods Mentioned

BETA
Acylation
electrophoresis
Fluorescence
transfect
FCS

Software Mentioned

RNAstructure
SHAPEKnots
Quantity One

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