Could the Inhibition of Endo-Lysosomal Two-Pore Channels (TPCs) by the Natural Flavonoid Naringenin Represent an Option to Fight SARS-CoV-2 Infection?

Naringenin is a powerful inhibitor of SARS-CoV-2 infection in vitro

“…Intriguingly, it has been shown that CoV infection depends on trafficking of virions to lysosomal compartments and processing of the S protein by lysosomal proteases is required for productive entry to occur. In this context, the role played by endo-lysosomal TPCs on CoV biology and the feasibility of blocking the intracellular pathway of the virus by inhibiting these channels was preliminarily inferred by our group [ [3] , [4] , [5] ] and confirmed by other authors [ 6 –8]. Genetic ablation of TPCs or TPC blockers have been previously shown to reduce infectivity affecting trafficking through the endo-lysosomal system of Ebola virus and MERS-CoV [9,10].…”

A review on possible mechanistic insights of Nitazoxanide for repurposing in COVID-19

“…Another proposed mechanism is the ability of nitazoxanide to interact with cysteine residues through S-nitrosylation ( Andrade and Reed, 2015 ; Bekendam et al, 2018 ; Goldman, 2010 ), which can hinder the irreversible inhibition of the kinases AAK1 and GAK by interaction with their cysteine residues Cys193 and Cys190 respectively ( Sorrell et al, 2016 ). These two kinases along with phosphatidylinositol 3-phosphate5-kinase (PIKFYVE) initiates early endosome formation and causes synthesis of phosphatidylinositol-3,5-bisphosphate [PI(3,5)P2] (Phosphoinositides) ( Kang et al, 2020 ; Ou et al, 2020 ), which activates two pore segment channel 2 (TPC2), a calcium channel expressed in lysosomal membranes ( Filippini et al, 2020 ; Grimm and Tang, 2020 ). TPC2 maintains Ca 2+ homeostasis and the Ca 2+ release from this channel is controlled by nicotinic acid adenine dinucleotide phosphate (NAADP), phosphoinositide and mTOR (X.…”

Lysosomal ion channels involved in cellular entry and uncoating of enveloped viruses: Implications for therapeutic strategies against SARS-CoV-2

“…Other cellular factors such as the lysosomal TPC2 (two-pore channel 2) induce the fusion process and release of viruses from the endolysosomal compartments to the cytoplasm [ 18 ]. TPC2 has also been shown to be required for release of the SARS-CoV-2 genome into target cells [ 19 ], although the specific role of TPC2 in virus escape into the cytoplasm is not completely clear [ [20] , [21] , [22] , [23] ]. Another lysosomal ion channel, TRPML2 (the second member of the mammalian mucolipin TRP channel subfamily), can affect viral entry by enhancing the efficiency of viral trafficking in the endosomal system [ 24 ].…”

“…Viruses have developed strategies to exploit host cell machinery and organelles to promote viral infection. Experiments have shown that entry of SARS-CoV-2 into host cells is mainly mediated by endocytosis, and is closely related to lysosomes [ 19 , 22 , 104 , 105 ]. More specifically, TPC2 is critical for SARS-CoV-2 infection, which supports the notion that lysosomal ion channels may be targets for therapeutic strategies against SARS-CoV-2.…”