A group from Università del Piemonte Orientale, Department of Health Sciences, Novara, Italy, etc. has reported that SARS-CoV-2 infection could be prevented by targeting autophagy processes with natural products such as Berberine, Baicalin, Resveratrol, Catechin, etc.
The mechanisms through which SARS-CoV-2 enter the cells, replicate within, and exit from them are are thought to be as follows.
(1) In brief, the main path for virus entry is via clathrin-mediated or clathrin/caveolae-independent endocytosis. The endocytosed virus can be delivered to the autophagy-lysosomal organelles for degradation. However, the virus RNA can escape from endocytic vesicles (upon cathepsin L-mediated processing of S and virus envelope-membrane fusion), and relocate in the cytoplasm.
(2) Additionally, the virus may enter the cell by lipid blending of the virus envelope and the host cell membrane. Cells expressing ACE2 are specifically targeted by SARS-CoV-2 through the interaction with S protein RBD.
(3) Whichever the path used for entering the cell, the cleavage of the S protein into the subunits S1 and S2 by host proteases such as endosomal cathepsin L, furin, trypsin, transmembrane protease serine protease 2 (TMPRSS-2), or human airway trypsin-like protease is an obligated step for allowing the fusion between the viral envelope and host cell membranes (either endosomal or plasma membrane) and the release of the genome into the cytoplasm.
Accordingly, inhibition of this proteolytic step greatly reduces the cellular viral load. The followings are typical natural products used for this purpose.
Berberine significantly interacts with SARS-CoV-2 3CLPRO, S protein, and ACE2 receptor, suggesting that Berberine could prevent viral entry and fusion and interfere with the autophagy processes and the biogenesis of double-membrane vesicle by affecting the 3CLPRO-mediated generation of nsps 4–16.
Baicalin and Baicalein
Baicalin interacts with the SARS-CoV-2 S and PLPRO, nsp4, and 3CLPRO proteins, suggesting another way to prevent the induction of autophagy
Resveratrol and its derivatives to strongly and stably block SARS-CoV-2 proteins PLPRO, RdRp, and S protein. Resveratrol could act as an ACE2 receptor inhibitor, preventing the formation of the S1/ACE2 complex and viral endocytosis, and double-membrane vesicles biogenesis. Furthermore, Resveratrol could impact the autophagic process through inhibition of PLPRO-mediated generation of nsps.
Catechin interferes with SARS-CoV-2 infection and replication by neutralizing 3CLPRO, S protein RBD, ACE2, S/ACE2 complex, cathepsin L, nsp6, and N protein. Tea polyphenols, including epigallocatechin-3-O-gallate (EGCG) and theaflavin 3,3’di-gallate, can strongly dock to 3CLPRO, S protein, S/ACE2 complex, PLPRO, and RdRp.
procyanidins significantly interacts with SARS-CoV-2 3CLPRO, nsp1, nsp2, PLPRO, nsp4, nsp6, nsp7, nsp8, nsp9, nsp10, RdRp, helicase, exon N, NendoU, 2′-O-MT, ORF3a, E protein, M protein, ORF6, ORF7a, ORF8, N protein, ORF10, ACE2, and S protein.