Andrographolide Derivatives Target the KEAP1/NRF2 Axis and Possess Potent Anti-SARS-CoV-2 Activity |
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| Authors: | Dr. Bianca Schulte Maria König Prof. Dr. Beate I. Escher Sophie Wittenburg Matic Proj Valentina Wolf Carina Lemke Dr. Gregor Schnakenburg Prof. Dr. Izidor Sosič Prof. Dr. Hendrik Streeck Prof. Dr. Christa E. Müller Prof. Dr. Michael Gütschow Dr. Christian Steinebach |
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| Affiliation: | 1. Institute of Virology, University Hospital Bonn, Venusberg-Campus 1, 53127 Bonn, Germany;2. Helmholtz Centre for Environmental Research–UFZ, Permoserstraße 15, 04318 Leipzig, Germany;3. Pharmaceutical Institute, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany;4. Faculty of Pharmacy, University of Ljubljana, Aškerčeva cesta 7, 1000 Ljubljana, Slovenia;5. Institute of Inorganic Chemistry, University of Bonn, Gerhard-Domagk-Str. 1, 53121 Bonn, Germany |
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| Abstract: | Naturally occurring compounds represent a vast pool of pharmacologically active entities. One of such compounds is andrographolide, which is endowed with many beneficial properties, including the activity against severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2). To initiate a drug repurposing or hit optimization campaign, it is imperative to unravel the primary mechanism(s) of the antiviral action of andrographolide. Here, we showed by means of a reporter gene assay that andrographolide exerts its anti-SARS-CoV-2 effects by inhibiting the interaction between Kelch-like ECH-associated protein 1 (KEAP1) and nuclear factor erythroid 2-related factor 2 (NRF2) causing NRF2 upregulation. Moreover, we demonstrated that subtle structural modifications of andrographolide could lead to derivatives with stronger on-target activities and improved physicochemical properties. Our results indicate that further optimization of this structural class is warranted to develop novel COVID-19 therapies. |
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| Keywords: | SARS-CoV-2 andrographolide KEAP1/NRF2 natural products medicinal chemistry |
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