Abstract
Antiviral drug resistance in influenza infections has been a major threat to public health. To develop a broad-spectrum inhibitor of influenza to combat the problem of drug resistance, we previously identified the highly conserved E339...R416 salt bridge of the nucleoprotein trimer as a target and compound 1 as an inhibitor disrupting the salt bridge with an EC50 = 2.7 μM against influenza A (A/WSN/1933). We have further modified this compound via a structure-based approach and performed antiviral activity screening to identify compounds 29 and 30 with EC50 values of 110 and 120 nM, respectively, and without measurable host cell cytotoxicity. Compared to the clinically used neuraminidase inhibitors, these two compounds showed better activity profiles against drug-resistant influenza A strains, as well as influenza B, and improved survival of influenza-infected mice.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Aniline Compounds / chemical synthesis
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Aniline Compounds / metabolism
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Aniline Compounds / pharmacology*
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Animals
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Antiviral Agents / chemical synthesis
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Antiviral Agents / metabolism
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Antiviral Agents / pharmacology*
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Binding Sites / drug effects
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Female
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Influenza A virus / chemistry*
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Mice, Inbred BALB C
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Molecular Docking Simulation
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Molecular Structure
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Nucleocapsid Proteins
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Protein Binding
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Protein Multimerization / drug effects*
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RNA-Binding Proteins / metabolism*
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Static Electricity
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Structure-Activity Relationship
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Thiazoles / chemical synthesis
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Thiazoles / metabolism
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Thiazoles / pharmacology*
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Viral Core Proteins / metabolism*
Substances
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Aniline Compounds
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Antiviral Agents
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NP protein, Influenza A virus
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Nucleocapsid Proteins
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RNA-Binding Proteins
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Thiazoles
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Viral Core Proteins