Stabilization and improvement of a promising influenza antiviral: Making a PAIN PAINless
journal contributionposted on 2023-01-12, 19:26 authored by Aleksandar Antanasijevic, Nicholas J. Hafeman, Smanla Tundup, Carolyn Kingsley, Rama K. Mishra, Lijun RongLijun Rong, Balaji Manicassamy, Duncan WardropDuncan Wardrop, Michael CaffreyMichael Caffrey
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.
NMR-based discovery of influenza hemagglutinin probes | Funder: National Institute of Allergy and Infectious Diseases | Grant ID: R21AI101676
CitationAntanasijevic, A., Hafeman, N. J., Tundup, S., Kingsley, C., Mishra, R. K., Rong, L., Manicassamy, B., Wardrop, D.Caffrey, M. (2016). Stabilization and improvement of a promising influenza antiviral: Making a PAIN PAINless. ACS Infectious Diseases, 2(9), 608-615. https://doi.org/10.1021/acsinfecdis.6b00046
PublisherAmerican Chemical Society (ACS)
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glycoproteinhemagglutininmolecular dynamicsNMRTBHQviral entryEmerging Infectious DiseasesInfectious DiseasesPneumonia & InfluenzaInfluenza5 Development of treatments and therapeutic interventions5.1 PharmaceuticalsAntioxidantsAntiviral AgentsHemagglutinin Glycoproteins, Influenza VirusHumansHydroquinonesInfluenza A virusInfluenza, HumanMolecular Dynamics SimulationStructure-Activity RelationshipMedical Microbiology