Stabilization and Improvement of a Promising Influenza Antiviral: Making a PAIN PAINless

Aleksandar Antanasijevic; Nicholas J Hafeman; Smanla Tundup; Carolyn Kingsley; Rama K Mishra; Lijun Rong; Balaji Manicassamy; Duncan Wardrop; Michael Caffrey

doi:10.1021/acsinfecdis.6b00046

Journal article

Stabilization and Improvement of a Promising Influenza Antiviral: Making a PAIN PAINless

Aleksandar Antanasijevic, Nicholas J Hafeman, Smanla Tundup, Carolyn Kingsley, Rama K Mishra, Lijun Rong, Balaji Manicassamy, Duncan Wardrop and Michael Caffrey

ACS infectious diseases, Vol.2(9), pp.608-615

09/09/2016

DOI: 10.1021/acsinfecdis.6b00046

PMID: 27759373

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Abstract

The viral envelope protein hemagglutinin (HA) plays a critical role in influenza entry and thus is an attractive target for novel therapeutics. The small molecule tert-butylhydroquinone (TBHQ) has previously been shown to bind to HA and inhibit HA-mediated entry with low micromolar potency. However, enthusiasm for the use of TBHQ has diminished due to the compound's antioxidant properties. In this work we show that the antioxidant properties of TBHQ are not responsible for the inhibition of HA-mediated entry. In addition, we have performed a structure-activity relationship (SAR) analysis of TBHQ derivatives. We find that the most promising compound, 3-tert-butyl-4-methoxyphenol, exhibits enhanced potency (IC = 0.6 μM), decreased toxicity (CC = 340 μM), and increased stability (t > 48 h). Finally, we have characterized the binding properties of 3-tert-butyl-4-methoxyphenol using NMR and molecular dynamics to guide future efforts for chemical optimization.

Antiviral Agents - pharmacology

Antioxidants - chemistry

Humans

Hydroquinones - chemistry

Influenza A virus - genetics

Structure-Activity Relationship

Antioxidants - pharmacology

Hydroquinones - pharmacology

Hemagglutinin Glycoproteins, Influenza Virus - metabolism

Molecular Dynamics Simulation

Hemagglutinin Glycoproteins, Influenza Virus - genetics

Influenza A virus - metabolism

Antiviral Agents - chemistry

Influenza, Human - virology

Influenza A virus - drug effects

Details

Title: Subtitle: Stabilization and Improvement of a Promising Influenza Antiviral: Making a PAIN PAINless
Creators: Aleksandar Antanasijevic - Department of Biochemistry & Molecular Genetics, University of Illinois at Chicago , 900 South Ashland Avenue, Chicago, Illinois 60607, United States
Nicholas J Hafeman - Department of Chemistry, University of Illinois at Chicago , 845 West Taylor Street, Chicago, Illinois 60607, United States
Smanla Tundup - Department of Microbiology and Immunology, University of Chicago , 920 East 58th Street, Chicago, Illinois 60637, United States
Carolyn Kingsley - Department of Biochemistry & Molecular Genetics, University of Illinois at Chicago , 900 South Ashland Avenue, Chicago, Illinois 60607, United States
Rama K Mishra - Center for Molecular Innovation and Drug Discovery, Northwestern University , 2135 Sheridan Road, Evanston, Illinois 60208, United States
Lijun Rong - Department of Microbiology & Immunology, University of Illinois at Chicago , 835 South Wolcott, Chicago, Illinois 60612, United States
Balaji Manicassamy - Department of Microbiology and Immunology, University of Chicago , 920 East 58th Street, Chicago, Illinois 60637, United States
Duncan Wardrop - Department of Chemistry, University of Illinois at Chicago , 845 West Taylor Street, Chicago, Illinois 60607, United States
Michael Caffrey - Department of Biochemistry & Molecular Genetics, University of Illinois at Chicago , 900 South Ashland Avenue, Chicago, Illinois 60607, United States
Resource Type: Journal article
Publication Details: ACS infectious diseases, Vol.2(9), pp.608-615
DOI: 10.1021/acsinfecdis.6b00046
PMID: 27759373
NLM abbreviation: ACS Infect Dis
ISSN: 2373-8227
eISSN: 2373-8227
Grant note: R21 AI101676 / NIAID NIH HHS
Language: English
Date published: 09/09/2016
Academic Unit: Microbiology and Immunology
Record Identifier: 9984083279702771

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