Journal article
Structural analyses reveal the mechanism of inhibition of influenza virus NS1 by two antiviral compounds
The Journal of biological chemistry, Vol.293(38), pp.14659-14668
09/21/2018
DOI: 10.1074/jbc.RA118.004012
PMCID: PMC6153301
PMID: 30076219
Abstract
The influenza virus is a significant public health concern causing 250,000-500,000 deaths worldwide each year. Its ability to change quickly results in the potential for rapid generation of pandemic strains for which most individuals would have no antibody protection. This pandemic potential highlights the need for the continuous development of new drugs against influenza virus. As an essential component and well established virulence determinant, NS1 (nonstructural protein 1) of influenza virus is a highly prioritized target for the development of anti-influenza compounds. Here, we used NMR to determine that the NS1 effector domain (NS1
) derived from the A/Brevig Mission/1/1918 (H1N1) strain of influenza (1918
) binds to two previously described anti-influenza compounds A9 (JJ3297) and A22. We then used X-ray crystallography to determine the three-dimensional structure of the 1918
NS1
Furthermore, we mapped the A9/A22-binding site onto our 1918
NS1
structure and determined that A9 and A22 interact with the NS1
in the hydrophobic pocket known to facilitate binding to the 30-kDa subunit of the cleavage and polyadenylation specificity factor (CPSF30), suggesting that the two compounds likely attenuate influenza replication by inhibiting the NS1
-CPSF30 interaction. Finally, our structure revealed that NS1
could dimerize via an interface that we termed the α
-α
dimer. Taken together, the findings presented here provide strong evidence for the mechanism of action of two anti-influenza compounds that target NS1 and contribute significant structural insights into NS1 that we hope will promote and inform the development and optimization of influenza therapies based on A9/A22.
Details
- Title: Subtitle
- Structural analyses reveal the mechanism of inhibition of influenza virus NS1 by two antiviral compounds
- Creators
- Alex B Kleinpeter - University of Alabama at BirminghamAlexander S Jureka - University of Alabama at BirminghamSally M Falahat - University of Alabama at BirminghamTodd J Green - University of Alabama at BirminghamChad M Petit - University of Alabama at Birmingham
- Resource Type
- Journal article
- Publication Details
- The Journal of biological chemistry, Vol.293(38), pp.14659-14668
- DOI
- 10.1074/jbc.RA118.004012
- PMID
- 30076219
- PMCID
- PMC6153301
- NLM abbreviation
- J Biol Chem
- ISSN
- 0021-9258
- eISSN
- 1083-351X
- Grant note
- T32 GM008111 / NIGMS NIH HHS R01 AI116738 / NIAID NIH HHS R01 AI134693 / NIAID NIH HHS S10 RR022994 / NCRR NIH HHS P30 CA013148 / NCI NIH HHS
- Language
- English
- Date published
- 09/21/2018
- Academic Unit
- Microbiology and Immunology
- Record Identifier
- 9984827337902771
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