Molecular Mechanisms of Possible Action of Phenolic Compounds in COVID-19 Protection and Prevention.

The worldwide outbreak of COVID-19 was caused by a pathogenic virus called Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2). Therapies against SARS-CoV-2 target the virus or human cells or the immune system. However, therapies based on specific antibodies, such as vaccines and monoclonal antibodies, may become inefficient enough when the virus changes its antigenicity due to mutations. Polyphenols are the major class of bioactive compounds in nature, exerting diverse health effects based on their direct antioxidant activity and their effects in the modulation of intracellular signaling. There are currently numerous clinical trials investigating the effects of polyphenols in prophylaxis and the treatment of COVID-19, from symptomatic, via moderate and severe COVID-19 treatment, to anti-fibrotic treatment in discharged COVID-19 patients. Antiviral activities of polyphenols and their impact on immune system modulation could serve as a solid basis for developing polyphenol-based natural approaches for preventing and treating COVID-19.

Construction and Investigation of Competing Endogenous RNA Networks and Candidate Genes Involved in SARS-CoV-2 Infection.

INTRODUCTION: The current COVID-19 pandemic caused by a novel coronavirus SARS-CoV-2 is a quickly developing global health crisis, yet the mechanisms of pathogenesis in COVID-19 are not fully understood. METHODS: The RNA sequencing data of SARS-CoV-2-infected cells was obtained from the Gene Expression Omnibus (GEO). The differentially expressed mRNAs (DEmRNAs), long non-coding RNAs (DElncRNAs), and microRNAs (DEmiRNAs) were identified by edgeR, and the SARS-CoV-2-associated competing endogenous RNA (ceRNA) network was constructed based on the prediction of bioinformatic databases. The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were conducted with the SARS-CoV-2-related DEmRNAs, and the protein-protein interaction network was also built basing on STRING database. The ROC analysis was performed for assessing the diagnostic efficiency of hub genes. RESULTS: The results indicated that SARS-CoV-2-related DEmRNAs were associated with the interferon signaling pathway and other antiviral processes, such as IFNL3, IFNL1 and CH25H. Our analysis suggested that lncRNA NEAT1 might regulate the host immune response through two miRNAs, hsa-miR-374-5p and hsa-miR-155-5p, which control the expression of SOCS1, IL6, IL1B, CSF1R, CD274, TLR6, and TNF. Additionally, IFI6, HRASLS2, IGFBP4 and PTN may be potential targets based on an analysis comparing the transcriptional responses of SARS-CoV-2 infection with that of other respiratory viruses. DISCUSSION: The unique ceRNA network identified potential non-coding RNAs and their possible targets as well as a new perspective to understand the molecular mechanisms of the host immune response to SARS-CoV-2. This study may also aid in the development of innovative diagnostic and therapeutic strategies.

Emergence and Re-emergence of Human Coronaviruses: Spike Protein as the Potential Molecular Switch and Pharmaceutical Target.

BACKGROUND: Recent emergence of COVID-19 caused by a new human coronavirus (CoV) strain (SARS-CoV-2), which originated from China, poses the future emergence of additional CoVs. In most of the cases of emergence of human CoVs, bats, palm civets, raccoon dogs and camels have been identified as the sources of human infections and as reservoir hosts. A review of comparative genomic and phenotypic characteristics of human CoV strains vis-à-vis their comparison with the corresponding animal isolates shall provide clues regarding the potential genomic, phenotypic and molecular factors responsible for host-switching, which may lead to prospective emergence and re-emergence of human CoV outbreaks in the future. METHODS: The seven known human strains of CoV were analyzed for the host and viral factors responsible for human outbreaks. The molecular factors responsible for host-susceptibility, virulence and pathogenesis were reviewed to predict the emergence and re-emergence of additional human CoV strains. CoV spike protein was evaluated as a potential viral receptor for host switching and the target for pharmaceutical design. RESULTS: A review of the factors associated with host-susceptibility, virulence and pathogenesis of seven known human CoV strains presents significant possibilities for the emergence of new CoV strain(s), leading to more human outbreaks. Continuous exposure of animals' handlers to the infected animals, environmental changes, improper sanitations, non-disposal of the solid waste and resumption of exotic animals markets provides favorable conditions for "host switching" and the emergence of new and potentially more virulent human CoV strains. Mutations in target genes (like spike protein), which facilitate the viral entry into the host-cells, provide a potential "molecular switch" for preferences of new host-receptors, genetic diversity, genetic-recombination and high virulence. Additionally, the clinical and environmental factors, asymptomatic carriers, the paucity of efficacious vaccines & therapeutics, inefficient disease management and infection control measures, lack of public awareness, and effective communication of information about more virulent human-adapted virus isolates are critical for the emergence of new and virulent SARS-CoV strains with high mortality and varied incubation period in the near future. Small molecules binding with conserved druggable regions of the CoV spike proteins may be effective against multiple strains of CoVs. CONCLUSION: High propensity of mutations and "molecular adaptations" in coronaviruses creates the hot spots and high potential for "host switching", leading to the emergence of more virulent strains of human CoVs. The public/global health agencies, medical communities and research scientists should be prepared for the emergence and re-emergence of new human CoV strain(s) leading to potential disease outbreaks. The inhibitors binding with conserved druggable regions of spike proteins from multiple strains CoV may have utility as broad-spectrum antiviral drugs to combat future emergence of CoVs.

Approaches and advances in the development of potential therapeutic targets and antiviral agents for the management of SARS-CoV-2 infection.

Virus onslaughts continue to spread fear and cause rampage across the world every now and then. The twenty first century is yet again witnessing a gross global pandemic, Coronavirus Disease 2019 (COVID-19) caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Globally no vaccines or drug specific to COVID-19 is available. Corona viruses have been in mutual relationship with humans and other hosts over many decades though aggressive zoonotic strains have caused havoc. Zoonotic emergent corona viruses prior to SARS-COV-2 included severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV), with the former leading to aggressive infectious spread and the later with high mortality rate. Although they emerged in the early period of the twenty first century, resilient biomedical and expertise in pharmaceutical domain could not appropriate any proprietary therapeutics. Studies envisaged towards curtailing their spread employed different stages of the virus life cycle with all zoonotic coronaviruses (CoVs) sharing genomic and structural similarities. Hence the strategies against SARS-CoV and MERS-CoV could prove effective against the recent outbreak of SAR-CoV-2. The review unravels key events involved in the lifecycle of SARS-CoV-2 while highlighting the possible avenues of therapy. The review also holds the scope in better understanding a broad-spectrum antivirals, monoclonal antibodies and small molecule inhibitors against viral glycoproteins, host cell receptor, viral mRNA synthesis, RNA-dependent RNA polymerase (RdRp) and viral proteases in order to design and develop antiviral drugs for SARS-CoV-2.

Unlocking COVID therapeutic targets: A structure-based rationale against SARS-CoV-2, SARS-CoV and MERS-CoV Spike.

There are no approved target therapeutics against SARS-CoV-2 or other beta-CoVs. The beta-CoV Spike protein is a promising target considering the critical role in viral infection and pathogenesis and its surface exposed features. We performed a structure-based strategy targeting highly conserved druggable regions resulting from a comprehensive large-scale sequence analysis and structural characterization of Spike domains across SARSr- and MERSr-CoVs. We have disclosed 28 main consensus druggable pockets within the Spike. The RBD and SD1 (S1 subunit); and the CR, HR1 and CH (S2 subunit) represent the most promising conserved druggable regions. Additionally, we have identified 181 new potential hot spot residues for the hSARSr-CoVs and 72 new hot spot residues for the SARSr- and MERSr-CoVs, which have not been described before in the literature. These sites/residues exhibit advantageous structural features for targeted molecular and pharmacological modulation. This study establishes the Spike as a promising anti-CoV target using an approach with a potential higher resilience to resistance development and directed to a broad spectrum of Beta-CoVs, including the new SARS-CoV-2 responsible for COVID-19. This research also provides a structure-based rationale for the design and discovery of chemical inhibitors, antibodies or other therapeutic modalities successfully targeting the Beta-CoV Spike protein.