Large Screening Identifies ACE2 Positively Correlates With NF-κB Signaling Activity and Targeting NF-κB Signaling Drugs Suppress ACE2 Levels

Abstract

Coronaviruses SARS-CoV-2 infected more than 156 million people and caused over 3 million death in the whole world, therefore a better understanding of the underlying pathogenic mechanism and the searching for more effective treatments were urgently needed. Angiotensin-converting enzyme 2 (ACE2) was the receptor for SARS-CoV-2 infection. In this study, we found that ACE2 was an interferon-stimulated gene (ISG) in human cell lines. By performing an ISG library screening, we found that ACE2 levels were positively regulated by multiple ISGs. Interestingly, ACE2 levels were highly correlated with ISGs-induced NF-κB activities, but not IFNβ levels. Furthermore, using an approved clinical durgs library, we found two clinical drugs, Cepharanthine and Glucosamine, significantly inhibited ACE2 level, IFNβ level, and NF-κB signaling downstream TNFα and IL6 levels. Our finding suggested the possible inhibitory effects of Cepharanthine and Glucosamine during SARS-CoV-2 infection and the subsequent inflammatory cytokine storm.

A New Butyrate Releaser Exerts a Protective Action against SARS-CoV-2 Infection in Human Intestine

“…Interestingly, a positive correlation between ACE2 and Nf-kB expression has been previously demonstrated, supporting the concept that targeting Nf-kB signaling can also inhibit ACE2 expression [ 56 ].…”

Inhibition of porcine deltacoronavirus entry and replication by Cepharanthine

“…Previous studies have shown that CEP acts on host cells to interfere with viral infection by affecting the expression of the viral receptor ACE2 (angiotensin-converting enzyme 2) ( Chitsike et al., 2021 ; Yan et al., 2021 ). In our study, we found that CEP interfered with PDCoV infection by acting on the host cell rather than the virus.…”

“…The binding affinity between the receptor and the viral protein affects the efficiency of viral infection in target cells ( Morizono et al., 2011 ). A previous study reported a significant reduction of symptoms in COVID-19 patients administered an angiotensin-converting enzyme inhibitor ( Yan et al., 2021 ). The mutation of key residues on APN significantly affects the infection efficiency of PDCoV ( Ji et al., 2022 ).…”

Impacts of the SARS-CoV-2 Spike Protein on the Innate Immune System: A Review

“…Using human cell models, Yan and his colleagues [ 77 ] found that the stimulation of RLRs with viral RNA mimic poly(I:C) or viral DNA mimic poly(dA:dT) increases the level of both ACE2 mRNA and protein, 13 ISGs promote its expression (especially ISG95), and finally, four of them (ISG10, ISG52, ISG71, and ISG95) can significantly enhance the NF-κB level. All these data suggest that ACE2 behaves like an ISG and its level correlates positively with NF-κB activities [ 77 ]. Thus, it is possible that the recognition of the Spike protein by TLR4 participates in the IFN-I response, which, in turn, improves ACE2 expression.…”

“…The type-I IFN response can be even more deleterious as ISG95 will induce ACE2 expression (while elevating NF-kB levels) [ 77 ], enabling the virus to infect cells that may not have originally been accessible to it, much like macrophages and peripheral blood immune cells [ 78 ]. The other potentially harmful effect of the type-I IFN response is the production of a truncated form of ACE2 (dACE2) via ISG15 [ 34 , 72 ].…”