scholarly journals Pathways and microRNAs bioinformatics analyses identifying possible existing therapeutics for COVID-19 treatment

2020 ◽  
Author(s):  
Laura Teodori ◽  
Piero Sestili ◽  
Valeria Madiai ◽  
Sofia Coppari ◽  
Daniele Fraternale ◽  
...  
Keyword(s):  
Angiotensin Converting Enzyme ◽  
In Silico ◽  
Molecular Mechanisms ◽  
Hdac Inhibitors ◽  
Converting Enzyme ◽  
Bioinformatics Analyses ◽  
Off Label ◽  
Host Virus Interactions ◽  
Virus Interactions ◽  
Ranked List

Abstract Over 180.000 SARS-COV-2 positive cases have been confirmed in Italy as April 20, with the number of deaths exceeding 23 thousand, making Italy the second Country for world COVID-19 deaths. Such enormous occurrence of infected and dead people raises the urgent demand of effective fast available treatments to control and diminish this pandemic. Discovering the cellular/molecular mechanisms of SARS-COV-2 pathogenicity is of paramount importance to understand how the infection becomes a disease and for therapeutically approaching it. From literature data, through a bioinformatics approach, an in silico analysis was performed, 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. We thus investigate on the signaling pathways modulated by the two proteins through query miRNet, the platform linking miRNAs, targets and functions. We predicted microRNAs (miRs), miR-335-5p and miR-26b-5p, as being modulated by Spike and ACE together with deacetylate histones pathway HDAC. Our results matched with the available clinical data. We hypothesize the current and EMA-approved, SARS-COV-2 off-label, HDAC inhibitors (HDACis) drugs may be repurposed to limit or block host-virus interactions. A ranked list of compounds is given that can be tested.

scholarly journals Pathways and microRNAs bioinformatics analyses identifying possible existing therapeutics for COVID-19 treatment

2020 ◽  
Author(s):  
Laura Teodori ◽  
Piero Sestili ◽  
Valeria Madiai ◽  
Sofia Coppari ◽  
Daniele Fraternale ◽  
...  
Keyword(s):  
Angiotensin Converting Enzyme ◽  
In Silico ◽  
Molecular Mechanisms ◽  
Hdac Inhibitors ◽  
Converting Enzyme ◽  
Bioinformatics Analyses ◽  
Off Label ◽  
Host Virus Interactions ◽  
Virus Interactions ◽  
Ranked List

Abstract Over 180.000 SARS-COV-2 positive cases have been confirmed in Italy as April 20, with the number of deaths exceeding 23 thousand, making Italy the second Country for world COVID-19 deaths. Such enormous occurrence of infected and dead people raises the urgent demand of effective fast available treatments to control and diminish this pandemic. Discovering the cellular/molecular mechanisms of SARS-COV-2 pathogenicity is of paramount importance to understand how the infection becomes a disease and for therapeutically approaching it. From literature data, through a bioinformatics approach, an in silico analysis was performed, 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. We thus investigate on the signaling pathways modulated by the two proteins through query miRNet, the platform linking miRNAs, targets and functions. We predicted microRNAs (miRs), miR-335-5p and miR-26b-5p, as being modulated by Spike and ACE together with deacetylate histones pathway HDAC. Our results matched with the available clinical data. We hypothesize the current and EMA-approved, SARS-COV-2 off-label, HDAC inhibitors (HDACis) drugs may be repurposed to limit or block host-virus interactions. A ranked list of compounds is given that can be tested.

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

2020 ◽  
Vol 11 ◽  
Author(s):  
Laura Teodori ◽  
Piero Sestili ◽  
Valeria Madiai ◽  
Sofia Coppari ◽  
Daniele Fraternale ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Bioinformatics Analysis ◽  
Hdac Inhibitors ◽  
Signalling Pathways ◽  
Bioinformatics Analyses ◽  
Off Label ◽  
Putative Target ◽  
Host Virus Interactions ◽  
Virus Interactions ◽  
Ranked List

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.

Thermodynamics of the interaction between the spike protein of severe acute respiratory syndrome- coronavirus-2 and the receptor of human angiotensin converting enzyme 2. Effects of possible ligands

2020 ◽  
Author(s):  
Cristina Garcia-Iriepa ◽  
Cecilia Hognon ◽  
Antonio Francés-Monerris ◽  
Isabel Iriepa ◽  
Tom Miclot ◽  
...  
Keyword(s):  
Angiotensin Converting Enzyme ◽  
Molecular Mechanisms ◽  
Molecular Design ◽  
Binding Free Energy ◽  
Transmembrane Protein ◽  
Spike Protein ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2 ◽  
Rational Molecular Design ◽  
Rational Evaluation

<div><p>Since the end of 2019, the coronavirus SARS-CoV-2 has caused more than 180,000 deaths all over the world, still lacking a medical treatment despite the concerns of the whole scientific community. Human Angiotensin-Converting Enzyme 2 (ACE2) was recently recognized as the transmembrane protein serving as SARS-CoV-2 entry point into cells, thus constituting the first biomolecular event leading to COVID-19 disease. Here, by means of a state-of-the-art computational approach, we propose a rational evaluation of the molecular mechanisms behind the formation of the complex and of the effects of possible ligands. Moreover, binding free energy between ACE2 and the active Receptor Binding Domain (RBD) of the SARS-CoV-2 spike protein is evaluated quantitatively, assessing the molecular mechanisms at the basis of the recognition and the ligand-induced decreased affinity. These results boost the knowledge on the molecular grounds of the SARS-CoV-2 infection and allow to suggest rationales useful for the subsequent rational molecular design to treat severe COVID-19 cases.</p></div>

scholarly journals The 5′ Untranslated Region of a Novel Infectious Molecular Clone of the Dicistrovirus Cricket Paralysis Virus Modulates Infection

2015 ◽  
Vol 89 (11) ◽  
pp. 5919-5934 ◽  
Author(s):  
Craig H. Kerr ◽  
Qing S. Wang ◽  
Kathleen Keatings ◽  
Anthony Khong ◽  
Douglas Allan ◽  
...  
Keyword(s):  
Untranslated Region ◽  
Molecular Mechanisms ◽  
Insect Cells ◽  
Infectious Clone ◽  
Virus Infectivity ◽  
Viral Translation ◽  
Content Type ◽  
Host Virus Interactions ◽  
Virus Interactions ◽  
Paralysis Virus

ABSTRACTDicistroviridaeare a family of RNA viruses that possesses a single-stranded positive-sense RNA genome containing two distinct open reading frames (ORFs), each preceded by an internal ribosome entry site that drives translation of the viral structural and nonstructural proteins, respectively. The type species,Cricket paralysis virus(CrPV), has served as a model for studying host-virus interactions; however, investigations into the molecular mechanisms of CrPV and other dicistroviruses have been limited as an established infectious clone was elusive. Here, we report the construction of an infectious molecular clone of CrPV. Transfection ofin vitro-transcribed RNA from the CrPV clone intoDrosophilaSchneider line 2 (S2) cells resulted in cytopathic effects, viral RNA accumulation, detection of negative-sense viral RNA, and expression of viral proteins. Transmission electron microscopy, viral titers, and immunofluorescence-coupled transwell assays demonstrated that infectious viral particles are released from transfected cells. In contrast, mutant clones containing stop codons in either ORF decreased virus infectivity. Injection of adultDrosophilaflies with virus derived from CrPV clones but not UV-inactivated clones resulted in mortality. Molecular analysis of the CrPV clone revealed a 196-nucleotide duplication within its 5′ untranslated region (UTR) that stimulated translation of reporter constructs. In cells infected with the CrPV clone, the duplication inhibited viral infectivity yet did not affect viral translation or RNA accumulation, suggesting an effect on viral packaging or entry. The generation of the CrPV infectious clone provides a powerful tool for investigating the viral life cycle and pathogenesis of dicistroviruses and may further understanding of fundamental host-virus interactions in insect cells.IMPORTANCEDicistroviridae, which are RNA viruses that infect arthropods, have served as a model to gain insights into fundamental host-virus interactions in insect cells. Further insights into the viral molecular mechanisms are hampered due to a lack of an established infectious clone. We report the construction of the first infectious clone of the dicistrovirus, cricket paralysis virus (CrPV). We show that transfection of the CrPV clone RNA intoDrosophilacells led to production of infectious particles that resemble natural CrPV virions and result in cytopathic effects and expression of CrPV proteins and RNA in infected cells. The CrPV clone should provide insights into the dicistrovirus life cycle and host-virus interactions in insect cells. Using this clone, we find that a 196-nucleotide duplication within the 5′ untranslated region of the CrPV clone increased viral translation in reporter constructs but decreased virus infectivity, thus revealing a balance that interplays between viral translation and replication.

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