Fig. 4.

Schematic representation of tizoxanide induced autophagy hindering SARS-CoV-2 genome synthesis. Tizoxanide (TIZ) activates Beclin1, PI3KCIII and AMPK which leads to activation of ULK1 inducing autophagosome formation. TIZ also increases cytosolic Ca²⁺ concentration through IP₃R by depleting ER Ca²⁺ store inducing ER stress and activating protective UPR signalling. TIZ causes conversion of LC3I to LC3II, degradation of p62/SQSTM1 and inhibits PI3KCI/Akt/mTOR signalling, all together promoting autophagy. AMPK, AMP-protein activated kinase; ER, Endoplasmic reticulum; IP₃R, Inositol trisphosphate receptor; LC3, Light chain 3; p62/SQSTM1, cargo receptor p62/sequestome1; PI3KCI, Phosphatidylinositol-3-kinase class I; PI3KCIII, Phosphatidylinositol-3-kinase class III; PI3KCI/Akt/mTOR, phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin; ULK1/2, Unc-51-like kinase-1/2; UPR, Unfolded protein response.