MicroRNAs Bioinformatics Analyses Identifying HDAC Pathway as a Putative Target for Existing Anti‐COVID‐19 Therapeutics

Teodori, Laura; Sestili, Piero; Madiai, Valeria; Coppari, Sofia; Fraternale, Daniele; Rocchi, Marco; Ramakrishna, Seeram; Albertini, Maria Cristina

doi:10.3389/fphar.2020.582003

Cited by 37 publications

(25 citation statements)

References 47 publications

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“…Teodori et al . carried out a bioinformatic analysis to show that the HDAC pathway is the key to the pathogenicity of SARS-CoV-2 [ 51 ]. They proposed that activation of AT1R (angiotensin II receptor type 1) by the excessive accumulation of angiotensin II (AngII) leads to the stimulation of HDACs that upregulate ACE2 expression.…”

Section: Discussionmentioning

confidence: 99%

Epigenetic targeting of the ACE2 and NRP1 viral receptors limits SARS-CoV-2 infectivity

et al. 2021

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Background SARS-CoV-2 uses the angiotensin-converting enzyme 2 (ACE2) and neuropilin-1 (NRP1) receptors for entry into cells, and the serine protease TMPRSS2 for S protein priming. Inhibition of protease activity or the engagement with ACE2 and NRP1 receptors has been shown to be an effective strategy for blocking infectivity and viral spreading. Valproic acid (VPA; 2-propylpentanoic acid) is an epigenetic drug approved for clinical use. It produces potent antiviral and anti-inflammatory effects through its function as a histone deacetylase (HDAC) inhibitor. Here, we propose VPA as a potential candidate to tackle COVID-19, in which rapid viral spread and replication, and hyperinflammation are crucial elements. Results We used diverse cell lines (HK-2, Huh-7, HUVEC, Caco-2, and BEAS-2B) to analyze the effect of VPA and other HDAC inhibitors on the expression of the ACE-2 and NRP-1 receptors and their ability to inhibit infectivity, viral production, and the inflammatory response. Treatment with VPA significantly reduced expression of the ACE2 and NRP1 host proteins in all cell lines through a mechanism mediated by its HDAC inhibitory activity. The effect is maintained after SARS-CoV-2 infection. Consequently, the treatment of cells with VPA before infection impairs production of SARS-CoV-2 infectious viruses, but not that of other ACE2- and NRP1-independent viruses (VSV and HCoV-229E). Moreover, the addition of VPA 1 h post-infection with SARS-CoV-2 reduces the production of infectious viruses in a dose-dependent manner without significantly modifying the genomic and subgenomic messenger RNAs (gRNA and sg mRNAs) or protein levels of N protein. The production of inflammatory cytokines (TNF-α and IL-6) induced by TNF-α and SARS-CoV-2 infection is diminished in the presence of VPA. Conclusions Our data showed that VPA blocks three essential processes determining the severity of COVID-19. It downregulates the expression of ACE2 and NRP1, reducing the infectivity of SARS-CoV-2; it decreases viral yields, probably because it affects virus budding or virions stability; and it dampens the triggered inflammatory response. Thus, administering VPA could be considered a safe treatment for COVID-19 patients until vaccines have been rolled out across the world.

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Section: Discussionmentioning

confidence: 99%

Epigenetic targeting of the ACE2 and NRP1 viral receptors limits SARS-CoV-2 infectivity

et al. 2021

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“…Each miRNA can target multiple messenger RNAs (mRNAs), and altogether, miRNAs are predicted to regulate more than half of the human transcriptome (Friedman et al, 2009). Recent evidence has shown that different diseases, including COVID-19, lead to distinct complements of miRNAs in the blood (Nersisyan et al, 2020;Sac ¸ar Demirci and Adan, 2020;Teodori et al, 2020). These circulating miRNAs are highly stable and have the potential to be used for minimally invasive detection, as biomarkers, and as therapeutic targets (Tribolet et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

Role of miR-2392 in driving SARS-CoV-2 infection

et al. 2021

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MicroRNAs (miRNAs) are small non-coding RNAs involved in post-transcriptional gene regulation that have a major impact on many diseases and provides an exciting avenue towards antiviral therapeutics. From patient transcriptomic data, we determined a circulating miRNA, miR-2392, is directly involved with SARS-CoV-2 machinery during host infection. Specifically, we show that miR-2392 is key in driving downstream suppression of mitochondrial gene expression, increasing inflammation, glycolysis, and hypoxia as well as promoting many symptoms associated with COVID-19 infection. We demonstrate miR-2392 is present in the blood and urine of patients positive for COVID-19, but not present in patients negative for COVID-19. These findings indicate the potential for developing a minimally invasive COVID-19 detection method. Lastly, using in vitro human and in vivo hamster models, we design a miRNA-based antiviral therapeutic that targets miR-2392, significantly reduces SARS-CoV-2 viability in hamsters and may potentially inhibit a COVID-19 disease state in humans.

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“…Many of these docking mechanisms are pH dependent. So far, studies show that SARS-CoV-2 uses the ACE2 receptor as a main docking protein (Yang et al, 2020;Teodori et al, 2020). ACE2 is essential for SARS-CoV-2 fusion, but it is uncertain whether ACE2 interactions are enough for SARS-CoV-2 binding.…”

Section: Increased External Ph May Disadvantage Virus Infectionmentioning

confidence: 99%

Extracellular pH, osmolarity, temperature and humidity could discourage SARS-CoV-2 cell docking and propagation via intercellular signaling pathways

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Sestili

Madiai

et al. 2021

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The COVID-19 pandemic and its virus variants continue to pose a serious and long-lasting threat worldwide. To combat the pandemic, the world’s largest COVID-19 vaccination campaign is currently ongoing. As of July 19th 2021, 26.2% of the world population has received at least one dose of a COVID-19 vaccine (1.04 billion), and one billion has been fully vaccinated, with very high vaccination rates in countries like Israel, Malta, and the UEA. Conversely, only 1% of people in low-income countries have received at least one dose with examples of vaccination frequency as low as 0.07% in the Democratic Republic of Congo. It is thus of paramount importance that more research on alternate methods to counter cell infection and propagation is undertaken that could be implemented in low-income countries. Moreover, an adjunctive therapeutic intervention would help to avoid disease exacerbation in high-rate vaccinated countries too. Based on experimental biochemical evidence on viral cell fusion and propagation, herein we identify (i) extracellular pH (epH), (ii) temperature, and (iii) humidity and osmolarity as critical factors. These factors are here in discussed along with their implications on mucus thick layer, proteases, abundance of sialic acid, vascular permeability and exudate/edema. Heated, humidified air containing sodium bicarbonate has long been used in the treatment of certain diseases, and here we argue that warm inhalation of sodium bicarbonate might successfully target these endpoints. Although we highlight the molecular/cellular basis and the signalling pathways to support this intervention, we underscore the need for clinical investigations to encourage further research and clinical trials. In addition, we think that such an approach is also important in light of the high mutation rate of this virus originating from a rapid increase.

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MicroRNAs Bioinformatics Analyses Identifying HDAC Pathway as a Putative Target for Existing Anti‐COVID‐19 Therapeutics

Cited by 37 publications

References 47 publications

Epigenetic targeting of the ACE2 and NRP1 viral receptors limits SARS-CoV-2 infectivity

Epigenetic targeting of the ACE2 and NRP1 viral receptors limits SARS-CoV-2 infectivity

Role of miR-2392 in driving SARS-CoV-2 infection

Extracellular pH, osmolarity, temperature and humidity could discourage SARS-CoV-2 cell docking and propagation via intercellular signaling pathways

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