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  Identification of Myricetin as an Ebola Virus VP35-Double-Stranded RNA Interaction Inhibitor through a Novel Fluorescence-Based Assay

Daino, G. L., Frau, A., Sanna, C., Rigano, D., Distinto, S., Madau, V., et al. (2018). Identification of Myricetin as an Ebola Virus VP35-Double-Stranded RNA Interaction Inhibitor through a Novel Fluorescence-Based Assay. Biochemistry, 57(44), 6367-6378. doi:10.1021/acs.biochem.8b00892.

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 Creators:
Daino, Gian Luca1, Author
Frau, Aldo1, Author
Sanna, Cinzia1, Author
Rigano, Daniela1, Author
Distinto, Simona1, Author
Madau, Veronica1, Author
Espoito, Francesca1, Author
Fanunza, Elisa1, Author
Bianco, Giulia1, Author
Taglialatela-Scafati, Orazio1, Author
Zinzula, Luca2, Author              
Maccioni, Elias1, Author
Corona, Angela1, Author
Tramontano, Enzo1, Author
Affiliations:
1external, ou_persistent22              
2Baumeister, Wolfgang / Molecular Structural Biology, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565142              

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Free keywords: DOUBLE-STRANDED-RNA; INFLUENZA-A VIRUS; VP35 PROTEIN; INTERFERON ANTAGONISM; REVERSE-TRANSCRIPTASE; MARBURG-VIRUS; BIOLOGICAL-ACTIVITY; BINDING EXPERIMENTS; HYPERICUM-HIRCINUM; NATURAL-PRODUCTSBiochemistry & Molecular Biology;
 Abstract: Ebola virus (EBOV) is a filovirus that causes a severe and rapidly progressing hemorrhagic syndrome; a recent epidemic illustrated the urgent need for novel therapeutic agents because no drugs have been approved for treatment of Ebola virus. A key contribution to the high lethality observed during EBOV outbreaks comes from viral evasion of the host antiviral innate immune response in which viral protein VP35 plays a crucial role, blocking interferon type I production, first by masking the viral double-stranded RNA (dsRNA) and preventing its detection by the pattern recognition receptor RIG-I. Aiming to identify inhibitors of the interaction of VP35 with the viral dsRNA, counteracting the VP35 viral innate immune evasion, we established a new methodology for high-yield recombinant VP35 (rVP35) expression and purification and a novel and robust fluorescence-based rVP35-RNA interaction assay (Z' factor of 0.69). Taking advantage of such newly established methods, we screened a small library of Sardinian natural extracts, identifying Limonium morisianum as the most potent inhibitor extract. A bioguided fractionation led to the identification of myricetin as the component that can inhibit rVP35-dsRNA interaction with an IC50 value of 2.7 mu M. Molecular docking studies showed that myricetin interacts with the highly conserved region of the VP35 RNA binding domain, laying the basis for further structural optimization of potent inhibitors of VP35-dsRNA interaction.

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Language(s): eng - English
 Dates: 2018
 Publication Status: Published in print
 Pages: 12
 Publishing info: -
 Table of Contents: -
 Rev. Type: -
 Degree: -

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Title: Biochemistry
Source Genre: Journal
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Publ. Info: Columbus, Ohio : American Chemical Society
Pages: - Volume / Issue: 57 (44) Sequence Number: - Start / End Page: 6367 - 6378 Identifier: ISSN: 0006-2960
CoNE: https://pure.mpg.de/cone/journals/resource/954925384103