SARS-CoV-2 falls within the same size range (60–140 nm) and shape (spherical)3 as commonly studied synthetic nanoparticles12,13. Therefore, it is possible that one of the mechanisms responsible for chloroquine-mediated effects against SARS-CoV-2 is a general decrease in the ability of cells to perform clathrin-mediated endocytosis of nanosized structures due to PICALM suppression (Fig. 1). Other Coronaviridae are known to enter host cells through receptor-mediated endocytosis, although direct fusion with the plasma membrane has also been reported. For example, the SARS-CoV virus identified in 2003 and the human coronavirus NL63 (HCoV-NL63) identified in 2004 bind to the angiotensin-converting enzyme 2 (ACE2) receptor, triggering endocytosis-driven cell entry14,15. Both clathrin-mediated and clathrin/caveolae-independent endocytosis mechanisms have been described for SARS-CoV entry in human cells16,17. SARS-CoV-2 might use similar ACE2-mediated mechanisms of cell entry
Moreover, chloroquine-induced prevention of endosome–lysosome fusion is likely to interfere with general endocytic trafficking, such as membrane receptor recycling, which is thought to be required for SARS-CoV-2 cellular entry. However, previous studies have revealed that chloroquine has therapeutic activity against SARS-CoV in cell culture but does not alter cell-surface levels of ACE27. Additionally, therapeutic doses of chloroquine did not substantially change the biosynthesis or glycosylation of the SARS-CoV spike glycoprotein7. On the contrary, terminal glycosylation of the ACE2 receptor was impaired, which may affect viral binding7. Chloroquine has been shown to display anti-SARS-CoV activity in cell culture even when administered after viral uptake7, suggesting that multiple beneficial mechanisms may be involved. Upon entry into cells via endocytosis, the spike protein on the surface of the virion must be cleaved by resident endosomal proteases such as cathepsins, which are activated upon acidification of the endosome. This cleavage induces a conformational change in the spike protein bringing the viral envelope and the endosomal membrane together to enable fusion. Chloroquine-induced inhibition of endosomal acidification is likely to alter this fusion event, stalling the virus in endosomes.
Reference & Source information: https://www.nature.com/
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