Histone deacetylase inhibitors suppress ACE2 and ABO simultaneously, suggesting a preventive potential against COVID-19

Abstract

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread worldwide as a pandemic throughout 2020. Since the virus uses angiotensin-converting enzyme 2 (ACE2) as a receptor for cellular entry, increment of ACE2 would lead to an increased risk of SARS-CoV-2 infection. At the same time, an association of the ABO blood group system with COVID-19 has also been highlighted: there is increasing evidence to suggest that non-O individuals are at higher risk of severe COVID-19 than O individuals. These findings imply that simultaneous suppression of ACE2 and ABO would be a promising approach for prevention or treatment of COVID-19. Notably, we have previously clarified that histone deacetylase inhibitors (HDACIs) are able to suppress ABO expression in vitro. Against this background, we further evaluated the effect of HDACIs on cultured epithelial cell lines, and found that HDACIs suppress both ACE2 and ABO expression simultaneously. Furthermore, the amount of ACE2 protein was shown to be decreased by one of the clinically-used HDACIs, panobinostat, which has been reported to reduce B-antigens on cell surfaces. On the basis of these findings, we conclude that panobinostat could have the potential to serve as a preventive drug against COVID-19.

Epigenetic perspectives associated with COVID-19 infection and related cytokine storm: an updated review

“…Several positively associated genes, along with ACE2, are also regulated by H3K27 acetylation. Studies have reported that HDAC can contribute to SARS-CoV-2 pathogenicity in several ways -i) HDAC upregulates ACE2 expression and promotes viral entry to the cells [107], ii) HDAC activates pro-inflammatory responses against viral infections and may give rise to CS [108] iii) HDAC activity accumulates Acetyle Co-A, which elevates the cholesterol level [109]. Increased cholesterol levels can promote viral entry to the cells.…”

FragDPI: a novel drug-protein interaction prediction model based on fragment understanding and unified coding

“…We have compiled a list of each drug target by reviewing the literature. PI3K-DELTA is mainly responsible for phosphorylating specific signaling molecules that regulate cell growth and division [28]. DPP-4 inhibitors are a class of drugs prescribed to control hyperglycemia in adults with type 2 diabetes.…”

Supportive therapy during COVID-19: The proposed mechanism of short-chain fatty acids to prevent cytokine storm and multi-organ failure

“…More interestingly, butyrate has shown inhibition of NF-kB signaling pathway and facilitates the expression of antiinflammatory cytokines such as IL-10 in mononuclear cells and neutrophils (31). Recently, it has been shown in gut epithelial organoids and in some gastric cells lines that butyrate can downregulate genes essential for SARS-CoV-2 infection (Ace2, Tmprss2) and can also upregulated other antiviral pathways (32,33). Altogether, all these studies provide strong evidence that SCFA and especially butyrate exhibit a worth-investigating anti-inflammatory action that might be used to prevent or alter the course of cytokine storm in critically ill COVID-19 patients.…”

“…These results have driven the hypothesis that butyrate could serve as a supportive therapy during COVID-19 infection. Preclinical investigations performed with gut epithelial organoids or gastric cell lines have shown downregulation of SARS-CoV-2 entry genes under butyrate treatment (32,33). Another level of proof-of-concept could be reached by investigating the effects of butyrate supplementation in a relevant mouse model of SARS-CoV-2 infection.…”