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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

8 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)608-615
Number of pages8
JournalACS Infectious Diseases
Issue number9
StatePublished - Jul 25 2016


  • NMR
  • TBHQ
  • glycoprotein
  • hemagglutinin
  • molecular dynamics
  • viral entry

ASJC Scopus subject areas

  • Infectious Diseases


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