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

doi:10.1021/acsinfecdis.6b00046

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

Biochemistry and Molecular Genetics

Research output: Contribution to journal › Article › peer-review

7 Scopus citations

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.

Original language	English (US)
Pages (from-to)	608-615
Number of pages	8
Journal	ACS Infectious Diseases
Volume	2
Issue number	9
DOIs	https://doi.org/10.1021/acsinfecdis.6b00046
State	Published - Jul 25 2016

Keywords

NMR
TBHQ
glycoprotein
hemagglutinin
molecular dynamics
viral entry

ASJC Scopus subject areas

Infectious Diseases

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1021/acsinfecdis.6b00046

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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.",

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author = "Aleksandar Antanasijevic and Hafeman, {Nicholas J.} and Smanla Tundup and Carolyn Kingsley and Mishra, {Rama K} and Lijun Rong and Balaji Manicassamy and Duncan Wardrop and Michael Caffrey",

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doi = "10.1021/acsinfecdis.6b00046",

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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 - NMR

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KW - hemagglutinin

KW - molecular dynamics

KW - viral entry

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Stabilization and improvement of a promising influenza antiviral: Making a PAIN PAINless

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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