Abstract
Over 313,000 SARS-CoV-2 positive cases have been confirmed in Italy as of 30 September 2020, and the number of deaths exceeding thirty-five thousand makes Italy among the list of most significantly affected countries in the world. Such an enormous occurrence of infections and death raises the urgent demand for effective available treatments. Discovering the cellular/molecular mechanisms of SARS-CoV-2 pathogenicity is of paramount importance to understand how the infection becomes a disease and how to plan any therapeutic approach. In this regard, we performed an in silico analysis to predict the putative virus targets and evidence the already available therapeutics. Literature experimental results identified angiotensin-converting enzyme ACE and Spike proteins particularly involved in COVID-19. Consequently, we investigated the signalling pathways modulated by the two proteins through query miRNet, the platform linking miRNAs, targets, and functions. Our bioinformatics analysis predicted microRNAs (miRs), miR-335-5p and miR-26b-5p, as being modulated by Spike and ACE together with histone deacetylate (HDAC) pathway. Notably, our results identified ACE/ACE2-ATR1-Cholesterol-HDAC axis signals that also matched with some available clinical data. We hypothesize that the current and EMA-approved, SARS-CoV-2 off-label HDAC inhibitors (HDACis) drugs may be repurposed to limit or block host-virus interactions. Moreover, a ranked list of compounds is provided for further evaluation for safety, efficacy, and effectiveness.
Highlights
The Coronavirus superfamily includes several human pathogens with large RNA-encoded genomes classified into alpha, beta- and gamma-coronavirus families
The main mechanisms and interactions surged from miRNet bioinformatics analysis connecting viral S-protein and angiotensin-converting enzyme 2 (ACE2) host receptor returned Histone Deacetylate (HDAC) pathway modulation strongly significant (p 0.0113) with miR-335-5p involvement in ACE and Spike gene expressions
It is known that ACE cleaves angiotensin I to generate angiotensin II, whereas ACE2 converts angiotensin II in the vasodilator angiotensin funtioning as a negative regulator of the renin-angiotensin (RAS) system (Imai et al, 2005)
Summary
The Coronavirus superfamily includes several human pathogens with large RNA-encoded genomes classified into alpha-, beta- and gamma-coronavirus families. The family’s rate of new virulent human pathogens has increased over the past years, and members of this family have since been identified, which include SARS-CoV (2003), HCoV NL63 (2004), HKU1 (2005), MERS-CoV (2012), and SARS-CoV-2 (previously named 2019-nCoV, 2019) Most of these are reported to involve severe respiratory tract infections. The mechanism underlying the antiviral effect of these latter drugs resides in the abundance of extra nitrogens: once they cross the membrane and enters an organelle, the organelle is prevented from reaching a lower pH, an event which disables the hydrolysis required for coronavirus replication Alongside this mechanism, chloroquine has been reported to cause an underglycosylation of ACE2. Randomized Controlled Trials (RCTs) showed that the treatment with hydroxychloroquine provides no benefits in COVID-19 patients (Ortolani and Pastorello, 2020)
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