Author/Editor		Schulte, Bianca; König, Maria; Escher, Beate I.; Wittenburg, Sophie; Proj, Matic; Wolf, Valentina; Lemke, Carina; Schnakenburg, Gregor; Sosič, Izidor; Streeck, Hendrik
Title		Andrographolide derivatives target the KEAP1/NRF2 axis and possess potent anti-SARS-CoV-2 activity
Type		članek
Vol. and No.		Letnik 17, št. 5, e202100732
Publication year		2022
Volume		str. 1-11
ISSN		1860-7187 - ChemMedChem
Language		eng
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.
Descriptors		Farmacevtska kemija Farmakologija SARS-CoV-2