Abstract
The RNA-dependent RNA polymerase of influenza A virus comprises conserved and independently-folded subdomains with defined functionalities. The N-terminal domain of the PA subunit (PAN) harbors the endonuclease function so that it can serve as a desired target for drug discovery. To identify a class of anti-influenza inhibitors that impedes PAN endonuclease activity, a screening approach that integrated the fluorescence resonance energy transfer based endonuclease inhibitory assay with the DNA gel-based endonuclease inhibitory assay was conducted, followed by the evaluation of antiviral efficacies and potential cytotoxicity of the primary hits in vitro and in vivo. A small-molecule compound ANA-0 was identified as a potent inhibitor against the replication of multiple subtypes of influenza A virus, including H1N1, H3N2, H5N1, H7N7, H7N9 and H9N2, in cell cultures. Combinational treatment of zanamivir and ANA-0 exerted synergistic anti-influenza effect in vitro. Intranasal administration of ANA-0 protected mice from lethal challenge and reduced lung viral loads in H1N1 virus infected BALB/c mice. In summary, ANA-0 shows potential to be developed to novel anti-influenza agents.
Highlights
The continuous zoonotic circulation and re-assortment potential of influenza A viruses in nature have been posing an enormous public health threat to humans[1,2,3]
Fluorescence signals were recorded in the presence or absence of a known PA endonuclease inhibitor DPBA36
The result suggested that the PA subunit (PAN) endonuclease activity was inhibited by dioxo-4-phenylbutanoic acid (DPBA)
Summary
The continuous zoonotic circulation and re-assortment potential of influenza A viruses in nature have been posing an enormous public health threat to humans[1,2,3]. The N-terminal domain of PA subunit (PAN) has been confirmed to accommodate the endonuclease activity residues, which is highly conserved among subtypes of influenza A virus and is able to fold functionally in vitro[12,13]. Substitutions in this functional domain, the catalytic residues, were expected to considerably reduce the viral fitness[14,15]. In this regard, the emergence of resistant virus mutants induced by PAN antivirals may be significantly delayed. An inhibitor(5Z)-2-[2-(2-oxoindol-3-yl)hydrazinyl]-5-(2-oxo-1H-indol-3-ylidene)-1,3-thiazol-4-one, designated ANA-0, exhibited potent and cross-subtype antiviral effects with high selectivity index
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
