The role of autophagy in controlling SARS‐CoV‐2 infection: An overview on virophagy‐mediated molecular drug targets

Sargazi, Saman; Sheervalilou, Roghayeh; Rokni, Mohsen; Shirvaliloo, Milad; Shahraki, Omolbanin; Rezaei, Nima

Autophagy‐dependent cell death is a prominent mechanism that majorly contributes to homeostasis by maintaining the turnover of organelles under stressful conditions. Several viruses, including coronaviruses (CoVs), take advantage of cellular autophagy to facilitate their own replication. Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) is a beta‐coronavirus (β‐CoVs) that mediates its replication through a dependent or independent ATG5 pathway using specific double‐membrane vesicles that can be considered as similar to autophagosomes. With due attention to several mutations in NSP6, a nonstructural protein with a positive regulatory effect on autophagosome formation, a potential correlation between SARS‐CoV‐2 pathogenesis mechanisms and autophagy can be expected. Certain medications, albeit limited in number, have been indicated to negatively regulate autophagy flux, potentially in a way similar to the inhibitory effect of β‐CoVs on the process of autophagy. However, there is no conclusive evidence to support their direct antagonizing effect on CoVs. Off‐target accumulation of a major fraction of FDA‐approved autophagy modulating drugs may result in adverse effects. Therefore, medications that have modulatory effects on autophagy could be considered as potential lead compounds for the development of new treatments against this virus. This review discusses the role of autophagy/virophagy in controlling SARS‐CoV‐2, focusing on the potential therapeutic implications.