Fig. 2.

Schematic representation of possible role of tizoxanide (TIZ)-inhibition of SARS-CoV-2 fusion and entry.

(A) Non-endosomal entry involves the proteolytic cleavage of SARS-CoV-2 spike proteins (S1/S2) by host cell proteases TMPRSS2 and furin. TIZ inhibits PDI and affects thiol-disulfide oxidoreductase switch in the ectodomains of TMPRSS2, and inhibition of PDI also inhibits MMPs activation required for furin action, (B) Endosomal entry involves the recognition and binding of RBD of SARS-CoV-2 spike proteins to the host cell receptors ACE2 and CD147 enabling receptor mediated endocytic entry. TIZ inhibits thiol-disulfide exchange mechanism essential for receptor interaction with RBD by inhibiting PDI. This PDI inhibition also hampers MMPs and intergrins activation required for CD-147 activity. TIZ also inhibits intracellular signalling MAPK/ERK, PI3K/Akt/mTOR and Wnt/β-catenin affecting SARS-CoV-2 fusion and entry. ACE2, Angiotensin converting enzyme 2; CD147, Cluster of differentiation 147; MAPK/ERK, Mitogen-activated protein kinase/extracellular signal-regulated kinase; MMPs, Matrix metalloproteinases; PDI, Protein disulfide isomerase; PI3K/Akt/mTOR, phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin; RBD, Receptor binding domain; TIZ, Tizoxanide; TMPRSS2, Transmembrane protease serine 2.