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
  • 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.
Products