TY - JOUR
T1 - Stabilization and improvement of a promising influenza antiviral
T2 - Making a PAIN PAINless
AU - Antanasijevic, Aleksandar
AU - Hafeman, Nicholas J.
AU - Tundup, Smanla
AU - Kingsley, Carolyn
AU - Mishra, Rama K
AU - Rong, Lijun
AU - Manicassamy, Balaji
AU - Wardrop, Duncan
AU - Caffrey, Michael
PY - 2016/7/25
Y1 - 2016/7/25
N2 - 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.
AB - 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.
KW - glycoprotein
KW - hemagglutinin
KW - molecular dynamics
KW - NMR
KW - TBHQ
KW - viral entry
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U2 - 10.1021/acsinfecdis.6b00046
DO - 10.1021/acsinfecdis.6b00046
M3 - Article
C2 - 27759373
AN - SCOPUS:85009064342
VL - 2
SP - 608
EP - 615
JO - ACS Infectious Diseases
JF - ACS Infectious Diseases
SN - 2373-8227
IS - 9
ER -