Material basis and pharmacodynamic mechanism of YangshenDingzhi granules in the intervention of viral pneumonia:Based on serum pharmacochemistry and network pharmacology

Background:YangshenDingzhi granules(YSDZ)are clinically effective in preventing and treating COVID-19.The present study elucidates the underlying mechanism of YSDZ intervention in viral pneumonia by employing serum pharmacochemistry and network pharmacology.Methods:The chemical constituents of YSDZ in the blood were examined using ultraperformance liquid chromatography-quadrupole/orbitrap high-resolution mass spectrometry(UPLC-Q-Exactive Orbitrap MS).Potential protein targets were obtained from the SwissTargetPrediction database,and the target genes associated with viral pneumonia were identified using GeneCards,DisGeNET,and Online Mendelian Inheritance in Man(OMIM)databases.The intersection of blood component-related targets and disease-related targets was determined using Venny 2.1.Protein-protein interaction networks were constructed using the STRING database.The Metascape database was employed to perform enrichment analyses of Gene Ontology(GO)functions and Kyoto Encyclopedia of Genes and Genomes(KEGG)signaling pathways for the targets,while the Cytoscape 3.9.1 software was utilized to construct drug-component-disease-target-pathway networks.Further,in vitro and in vivo experiments were performed to establish the therapeutic effectiveness of YSDZ against viral pneumonia.Results:Fifteen compounds and 124 targets linked to viral pneumonia were detected in serum.Among these,MAPK1,MAPK3,AKT1,EGFR,and TNF play significant roles.In vitro tests revealed that the medicated serum suppressed the replication of H1N1,RSV,and SARS-CoV-2 replicon.Further,in vivo testing analysis shows that YSDZ decreases the viral load in the lungs of mice infected with RSV and H1N1.Conclusion:The chemical constituents of YSDZ in the blood may elicit therapeutic effects against viral pneumonia by targeting multiple proteins and pathways.

SARS-CoV-2 cell entry and targeted antiviral development

Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)is the causative agent of the pandemic coronavirus disease 2019(COVID-19),which threatens human health and public safety.In the urgent campaign to develop anti-S ARS-CoV-2 therapies,the initial entry step is one of the most appealing targets.In this review,we summarize the current understanding of SARS-CoV-2 cell entry,and the development of targeted antiviral strategies.Moreover,we speculate upon future directions toward nextgeneration of SARS-CoV-2 entry inhibitors during the upcoming post-pandemic era.

Revisiting influenza A virus life cycle from a perspective of genome balance

Influenza A virus(IAV)genome comprises eight negative-sense RNA segments,of which the replication is well orchestrated and the delicate balance of multiple segments are dynamically regulated throughout IAV life cycle.However,previous studies seldom discuss these balances except for functional hemagglutinin-neuraminidase balance that is pivotal for both virus entry and release.Therefore,we attempt to revisit IAV life cycle by highlighting the critical role of“genome balance”.Moreover,we raise a“balance regression”model of IAV evolution that the virus evolves to rebalance its genome after reassortment or interspecies transmission,and direct a“balance compensation”strategy to rectify the“genome imbalance”as a result of artificial modifications during creation of recombinant IAVs.This review not only improves our understanding of IAV life cycle,but also facilitates both basic and applied research of IAV in future.

Allopregnanolone targets nucleoprotein as a novel influenza virus inhibitor

Influenza A virus(IAV)poses a global public health concern and remains an imminent threat to human health.Emerging antiviral resistance to the currently approved influenza drugs emphasizes the urgent need for new therapeutic entities against IAV.Allopregnanolone(ALLO)is a natural product that has been approved as an antidepressant drug.In the present study,we repurposed ALLO as a novel inhibitor against IAVs.Mechanistic studies demonstrated that ALLO inhibited virus replication by interfering with the nucleus translocation of viral nucleoprotein(NP).In addition,ALLO showed significant synergistic activity with compound 16,a hemagglutinin inhibitor of IAVs.In summary,we have identified ALLO as a novel influenza virus inhibitor targeting NP,providing a promising candidate that deserves further investigation as a useful anti-influenza strategy in the future.