2. Academic Validation
  3. Andrographolide Derivatives Target the KEAP1/NRF2 Axis and Possess Potent Anti-SARS-CoV-2 Activity

Andrographolide Derivatives Target the KEAP1/NRF2 Axis and Possess Potent Anti-SARS-CoV-2 Activity

  • ChemMedChem. 2022 Mar 4;17(5):e202100732. doi: 10.1002/cmdc.202100732.
Bianca Schulte 1,  Maria König 2,  Beate I Escher 2 3,  Sophie Wittenburg 4,  Matic Proj 5,  Valentina Wolf 4,  Carina Lemke 4,  Gregor Schnakenburg 6,  Izidor Sosič 5,  Hendrik Streeck 1 7,  Christa E Müller 4,  Michael Gütschow 4,  Christian Steinebach 4
Affiliations

Affiliations

  • 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 Center for Applied Geoscience, Eberhard Karls University Tübingen, 72076, Tübingen, Germany.
  • 4 Pharmaceutical Institute, University of Bonn, An der Immenburg 4, 53121, Bonn, Germany.
  • 5 Faculty of Pharmacy, University of Ljubljana, Aškerčeva cesta 7, 1000, Ljubljana, Slovenia.
  • 6 Institute of Inorganic Chemistry, University of Bonn, Gerhard-Domagk-Str. 1, 53121, Bonn, Germany.
  • 7 German Center for Infection Research (DZIF), Partner Site Bonn-Cologne, Germany.
PMID: 35099120 DOI: 10.1002/cmdc.202100732
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.

Keywords

KEAP1/NRF2; SARS-CoV-2; andrographolide; medicinal chemistry; natural products.

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