Figure 6

Proposed mechanism for antiviral activity of manassantin B toward coxsackievirus B3. Once coxsackievirus B3 (CVB3) infects host cells, virus particles are uncoated from their capsid protein and subsequently release viral RNA into the cytosol. Because viral replication occurs inside replication vesicles such as intracellular organelles, host pattern-associated molecular pattern sensor proteins, such as cGAS and MAVS, cannot adequately recognise their counterpart ligand. When manassantin B is administered to CVB3-infected cells, it can suppress mitochondrial electron transport chain (ETC) complex 1 and 5. Suppressed ETC results in increased mitochondrial ROS production and shutdown of mitochondrial function. In addition, mitochondria suppressed by manassantin B release their own DNA, which may be recognised by cGAS. Mitochondrial DNA-recognised cGAS synthesises cGAMP, which serves as a secondary messenger, by conjugating ATP and GTP. cGAMP binds with STING, resulting in STING activation and TBK-1 recruitment. Phosphorylated TBK-1 phosphorylates IRF-3, which dimerises, is imported into the nucleus, and serves as a transcription factor for antiviral gene expression. Finally, viral replication can be suppressed by antiviral gene expression, which is activated by manassantin B.