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DDX3 inhibitors show antiviral activity against positive-sense single-stranded RNA viruses but not against negative-sense single-stranded RNA viruses: The coxsackie B model. 2020

Paola Quaranta, and Giulia Lottini, and Giulia Chesi, and Flavia Contrafatto, and Roberta Russotto, and Lisa Macera, and Michele Lai, and Pietro Giorgio Spezia, and Annalaura Brai, and Maurizio Botta, and Giulia Freer, and Mauro Pistello

Retrovirus Centre, Department of Translational Medicine and New Technologies in Medicine and Surgery, University of Pisa, Italy.

Picornaviridae are positive-sense single stranded RNA viruses with a similar genomic structure lacking a cap at the 5' end, but with a highly structured 5'-untranslated region (UTR) containing an internal ribosome entry site (IRES). IRES allows ribosomes to be recruited by the viral RNA and initiate translation in a cap-independent manner. Coxsackie virus type B (CV-B) belong to Picornaviridae and are widespread in human population. They usually cause subclinical infections but, occasionally, also severe diseases with various clinical manifestations. CV-B have no specific therapy. DEAD-box polypeptide 3 (DDX3) is a member of the Asp-Glu-Ala-Asp (DEAD)-box family with an ATP-dependent RNA unwinding helicase activity. Recently, several positive-sense single strand RNA viruses have been shown to need DDX3 for their translation. Here, we show that several DDX3 inhibitors reduced CV-B replication and production of viral protein, particularly when added within 12 h of infection. Based on in vitro and in silico data, we hypothesized that DDX3 inhibitors hamper interaction between DDX3 and viral IRES in a stereodynamic fashion. Accordingly, the DDX3 inhibitors tested have no activity against the Vesicular Stomatitis virus and Measles virus, which are negative-sense single stranded RNA viruses and use cap-dependent translation. This study suggests that DDX3 is required by RNA viruses lacking a cap and show that this enzyme is a valuable target to design antiviral molecules against CV-B. Thus, DDX3 is dispensable for cap-dependent translation, but required for translation of transcripts containing secondary structure in their UTRs.

UI	MeSH Term	Description	Entries
D007624	KB Cells	This line KB is now known to be a subline of the ubiquitous KERATIN-forming tumor cell line HeLa. It was originally thought to be derived from an epidermal carcinoma of the mouth, but was subsequently found, based on isoenzyme analysis, HeLa marker chromosomes, and DNA fingerprinting, to have been established via contamination by HELA CELLS. The cells are positive for keratin by immunoperoxidase staining. KB cells have been reported to contain human papillomavirus18 (HPV-18) sequences.	HeLa-KB Cells,Cell, HeLa-KB,Cell, KB,Cells, HeLa-KB,Cells, KB,HeLa KB Cells,HeLa-KB Cell,KB Cell
D008459	Measles virus	The type species of MORBILLIVIRUS and the cause of the highly infectious human disease MEASLES, which affects mostly children.	Edmonston virus
D009690	Nucleic Acid Conformation	The spatial arrangement of the atoms of a nucleic acid or polynucleotide that results in its characteristic 3-dimensional shape.	DNA Conformation,RNA Conformation,Conformation, DNA,Conformation, Nucleic Acid,Conformation, RNA,Conformations, DNA,Conformations, Nucleic Acid,Conformations, RNA,DNA Conformations,Nucleic Acid Conformations,RNA Conformations
D010948	Viral Plaque Assay	Method for measuring viral infectivity and multiplication in CULTURED CELLS. Clear lysed areas or plaques develop as the VIRAL PARTICLES are released from the infected cells during incubation. With some VIRUSES, the cells are killed by a cytopathic effect; with others, the infected cells are not killed but can be detected by their hemadsorptive ability. Sometimes the plaque cells contain VIRAL ANTIGENS which can be measured by IMMUNOFLUORESCENCE.	Bacteriophage Plaque Assay,Assay, Bacteriophage Plaque,Assay, Viral Plaque,Assays, Bacteriophage Plaque,Assays, Viral Plaque,Bacteriophage Plaque Assays,Plaque Assay, Bacteriophage,Plaque Assay, Viral,Plaque Assays, Bacteriophage,Plaque Assays, Viral,Viral Plaque Assays
D002470	Cell Survival	The span of viability of a cell characterized by the capacity to perform certain functions such as metabolism, growth, reproduction, some form of responsiveness, and adaptability.	Cell Viability,Cell Viabilities,Survival, Cell,Viabilities, Cell,Viability, Cell
D004791	Enzyme Inhibitors	Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction.	Enzyme Inhibitor,Inhibitor, Enzyme,Inhibitors, Enzyme
D006801	Humans	Members of the species Homo sapiens.	Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000067556	Internal Ribosome Entry Sites	Sequences within MESSENGER RNA that enable PROTEIN TRANSLATION INITIATION independent of 5' CAPPED RNA.	Internal Ribosome Entry Site
D000085102	Positive-Strand RNA Viruses	RNA viruses that have their genetic material encoded in the form of single-stranded, positive-sense RNA. Unlike RETROVIRUSES they do not employ DNA intermediates in their life-cycle.	(+) Sense RNA Viruses,Group IV Single-Stranded RNA Viruses,Positive Sense RNA Viruses,Sense-Strand RNA Viruses,Group IV Single Stranded RNA Viruses,Positive Strand RNA Viruses,Positive-Strand RNA Virus,RNA Virus, Positive-Strand,RNA Virus, Sense-Strand,RNA Viruses, Positive-Strand,RNA Viruses, Sense-Strand,Sense Strand RNA Viruses,Sense-Strand RNA Virus
D000086103	Negative-Sense RNA Viruses	RNA viruses that have their genetic material encoded in the form of single-stranded, negative-sense RNA. Unlike RETROVIRUSES they do not employ DNA intermediates in their life-cycle	Antisense-Strand RNA Viruses,Group V Single-Stranded RNA Viruses,Antisense Strand RNA Viruses,Antisense-Strand RNA Virus,Group V Single Stranded RNA Viruses,Negative Sense RNA Viruses,Negative-Sense RNA Virus,RNA Virus, Negative-Sense,RNA Viruses, Antisense-Strand,RNA Viruses, Negative-Sense