Broad Spectrum Inhibitor of Influenza A and B Viruses Targeting the Viral Nucleoprotein

Kris M White; Pablo Abreu Jr; Hui Wang; Paul D De Jesus; Balaji Manicassamy; Adolfo García-Sastre; Sumit K Chanda; Robert J DeVita; Megan L Shaw

doi:10.1021/acsinfecdis.7b00120

Journal article

Broad Spectrum Inhibitor of Influenza A and B Viruses Targeting the Viral Nucleoprotein

Kris M White, Pablo Abreu Jr, Hui Wang, Paul D De Jesus, Balaji Manicassamy, Adolfo García-Sastre, Sumit K Chanda, Robert J DeVita and Megan L Shaw

ACS infectious diseases, Vol.4(2), pp.146-157

02/09/2018

DOI: 10.1021/acsinfecdis.7b00120

PMCID: PMC6145453

PMID: 29268608

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https://www.ncbi.nlm.nih.gov/pmc/articles/6145453View

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Abstract

S119 was a top hit from an ultrahigh throughput screen performed to identify novel inhibitors of influenza virus replication. It showed a potent antiviral effect (50% inhibitory concentration, IC = 20 nM) and no detectable cytotoxicity (50% cytotoxic concentration, CC > 500 μM) to yield a selectivity index greater than 25 000. Upon investigation, we found that S119 selected for resistant viruses carrying mutations in the viral nucleoprotein (NP). These resistance mutations highlight a likely S119 binding site overlapping with but not identical to that found for the compound nucleozin. Mechanism of action studies revealed that S119 affects both the oligomerization state and cellular localization of the NP protein which has an impact on viral transcription, replication, and protein expression. Through a hit-to-lead structure-activity relationship (SAR) study, we found an analog of S119, named S119-8, which had increased breadth of inhibition against influenza A and B viruses accompanied by only a small loss in potency. Finally, in vitro viral inhibition assays showed a synergistic relationship between S119-8 and oseltamivir when they were combined, indicating the potential for future drug cocktails.

Cell Line

Influenza A virus - physiology

Virus Replication - drug effects

Antiviral Agents - pharmacology

Gene Expression Regulation, Viral - drug effects

Influenzavirus B - drug effects

Humans

Influenzavirus B - physiology

Virus Internalization - drug effects

Drug Synergism

Microbial Sensitivity Tests

Viral Core Proteins - antagonists & inhibitors

Animals

Protein Binding

Molecular Structure

Influenza A virus - drug effects

Oseltamivir - pharmacology

Protein Aggregates - drug effects

Details

Title: Subtitle: Broad Spectrum Inhibitor of Influenza A and B Viruses Targeting the Viral Nucleoprotein
Creators: Kris M White - Department of Microbiology, Icahn School of Medicine at Mount Sinai , New York, New York 10029, United States
Pablo Abreu Jr - Department of Microbiology, Icahn School of Medicine at Mount Sinai , New York, New York 10029, United States
Hui Wang
Paul D De Jesus
Balaji Manicassamy - Department of Microbiology, Icahn School of Medicine at Mount Sinai , New York, New York 10029, United States
Adolfo García-Sastre - Department of Microbiology, Icahn School of Medicine at Mount Sinai , New York, New York 10029, United States
Sumit K Chanda
Robert J DeVita
Megan L Shaw - Department of Microbiology, Icahn School of Medicine at Mount Sinai , New York, New York 10029, United States
Resource Type: Journal article
Publication Details: ACS infectious diseases, Vol.4(2), pp.146-157
DOI: 10.1021/acsinfecdis.7b00120
PMID: 29268608
PMCID: PMC6145453
NLM abbreviation: ACS Infect Dis
ISSN: 2373-8227
eISSN: 2373-8227
Grant note: HHSN272201400008C / NIAID NIH HHS U01 AI074539 / NIAID NIH HHS R21 AI102169 / NIAID NIH HHS U19 AI106754 / NIAID NIH HHS R56 AI139015 / NIAID NIH HHS
Language: English
Date published: 02/09/2018
Academic Unit: Microbiology and Immunology
Record Identifier: 9984083264702771

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