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Small Molecule Compounds That Inhibit Antioxidant Response Gene Expression in an Inducer-Dependent Manner
journal contribution
posted on 2020-01-15, 18:34 authored by Megan
R. Edwards, Gai Liu, Sampriti De, Julien Sourimant, Colette Pietzsch, Britney Johnson, Gaya K. Amarasinghe, Daisy W. Leung, Alexander Bukreyev, Richard K. Plemper, Zachary Aron, Terry L. Bowlin, Donald T. Moir, Christopher F. BaslerMarburg virus (MARV)
causes severe disease in humans and is known
to activate nuclear factor erythroid 2-related factor 2 (Nrf2), the
major transcription factor of the antioxidant response. Canonical
activation of Nrf2 involves oxidative or electrophilic stress that
prevents Kelch-like ECH-associated protein 1 (Keap1) targeted degradation
of Nrf2, leading to Nrf2 stabilization and activation of the antioxidant
response. MARV activation of Nrf2 is noncanonical with the MARV VP24
protein (mVP24) interacting with Keap1, freeing Nrf2 from degradation.
A high-throughput screening (HTS) assay was developed to identify
inhibitors of mVP24-induced Nrf2 activity and used to screen more
than 55,000 compounds. Hit compounds were further screened against
secondary HTS assays for the inhibition of antioxidant activity induced
by additional canonical and noncanonical mechanisms. This pipeline
identified 14 compounds that suppress the response, dependent on the
inducer, with 50% inhibitory concentrations below 5 μM and selectivity
index values greater than 10. Notably, several of the identified compounds
specifically inhibit mVP24-induced Nrf2 activity.
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selectivity index values5 μ MactivationKelch-like ECH-associated protein 1compoundNrf 2 stabilizationHTSInducer-Dependent Manner Marburg virusMARV VP 24 proteinInhibit Antioxidant Response Gene ExpressionSmall Molecule Compoundsantioxidant responsemVP 24-induced Nrf 2 activityNrf 2factor erythroid 2-
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