posted on 2016-07-25, 00:00authored byAleksandar Antanasijevic, Nicholas J. Hafeman, Smanla Tundup, Carolyn Kingsley, Rama K. Mishra, Lijun Rong, Balaji Manicassamy, Duncan Wardrop, Michael 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.