LAUSR

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.