title: Stabilization and Improvement of a Promising Influenza Antiviral: Making a PAIN PAINless.
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 (IC50= 0.6 μM), decreased toxicity (CC50= 340 μM), and increased stability (t1/2> 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.
authors.affiliation: Department of Biochemistry & Molecular Genetics, University of Illinois at Chicago , 900 South Ashland Avenue, Chicago, Illinois 60607, United States.
authors.forename: Aleksandar
authors.initials: A
authors.lastname: Antanasijevic
authors.affiliation: Department of Chemistry, University of Illinois at Chicago , 845 West Taylor Street, Chicago, Illinois 60607, United States.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Hafeman
authors.affiliation: Department of Microbiology and Immunology, University of Chicago , 920 East 58th Street, Chicago, Illinois 60637, United States.
authors.forename: Smanla
authors.initials: S
authors.lastname: Tundup
authors.affiliation: Department of Biochemistry & Molecular Genetics, University of Illinois at Chicago , 900 South Ashland Avenue, Chicago, Illinois 60607, United States.
authors.forename: Carolyn
authors.initials: C
authors.lastname: Kingsley
authors.affiliation: Center for Molecular Innovation and Drug Discovery, Northwestern University , 2135 Sheridan Road, Evanston, Illinois 60208, United States.
authors.forename: Rama K
authors.initials: RK
authors.lastname: Mishra
authors.affiliation: Department of Microbiology & Immunology, University of Illinois at Chicago , 835 South Wolcott, Chicago, Illinois 60612, United States.
authors.forename: Lijun
authors.initials: L
authors.lastname: Rong
authors.affiliation: Department of Microbiology and Immunology, University of Chicago , 920 East 58th Street, Chicago, Illinois 60637, United States.
authors.forename: Balaji
authors.initials: B
authors.lastname: Manicassamy
authors.affiliation: Department of Chemistry, University of Illinois at Chicago , 845 West Taylor Street, Chicago, Illinois 60607, United States.
authors.forename: Duncan
authors.initials: D
authors.lastname: Wardrop
authors.affiliation: Department of Biochemistry & Molecular Genetics, University of Illinois at Chicago , 900 South Ashland Avenue, Chicago, Illinois 60607, United States.
authors.forename: Michael
authors.initials: M
authors.lastname: Caffrey
mesh_terms: D000975:Antioxidants / Q000737:chemistry / Q000494:pharmacology; D000998:Antiviral Agents / Q000737:chemistry* / Q000494:pharmacology; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006873:Hydroquinones / Q000737:chemistry* / Q000494:pharmacology; D009980:Influenza A virus / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D007251:Influenza, Human / Q000821:virology*; D056004:Molecular Dynamics Simulation; D013329:Structure-Activity Relationship
chemical_list: D000975:Antioxidants; D000998:Antiviral Agents; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D006873:Hydroquinones; C018855:2-tert-butylhydroquinone
keywords: NMR; TBHQ; glycoprotein; hemagglutinin; molecular dynamics; viral entry