The Antiviral Roles Of Cucurbit[7]uril And Enoxacin Against Diverse Rna Viruses

The emergence and re-emergence of RNA virus including influenza A virus,SARS-CoV,Ebola virus,Zika virus,and SARS-CoV2 outbreaks highlight the urgent need for broad-spectrum antivirals and specific antiviral agents.Polyamines,including putrescine,spermidine and spermine,are a class of positively charged small molecules derived from ornithine ubiquitously and abundantly present in cells Polyamines are required for infections of a wide range of RNA viruses,therefore may become good antiviral targets.Due to their abilities to complex with molecules of biological interest,a variety of macrocyclic host molecules have shown great potentials in biomedical applications during the recent decades.Among them,cyclodextrins(CDs)and their derivatives have been successfully developed into drug carriers or antidotes with biomedical and clinical applications.Cucurbit[n]urils as a family of macrocyclic oligomers of methylene-bridged glycolurils with the shape resembling that of a pumpkin,have emerged in pharmaceutical and biomedical sciences as synthetic receptors.Due to its appropriate size to accommodate a variety of guest molecules of biomedical interest and its superior water solubility,CB[7] has been extensively investigated as a potential carrier for drug molecules as the molecular encapsulation by CB[7] often improved the chemical stability and solubility of the included drug molecules,controlled their release,and modulated their toxicity and therapeutic efficacies.In this study,we uncovered for the first time that cucurbit[7]uril(CB[7]),a synthetic macrocyclic molecule,exhibited effective antiviral activity against diverse RNA viruses,including many important human pathogens,through competitively binding with polyamines.Our findings not only provide a promising broad-spectrum antiviral agent,but more importantly,offer a novel therapeutic strategy to fight against RNA viruses by supramolecular sequestration of polyamines.RNAi antiviral pathway has been proved to be a positive innate immune pathway against virus infection in mammals.The nonstructure protein 3A has been proved as a VSR of EV-A71 to antagonize host RNAi antiviral pathway.Peptide ER-DRI targeting3 A of EV-A71 can trigger host RNAi antiviral pathway to inhibit virus replication.Small molecular Enoxacin as a RNAi enhancer has been proved to enhance RNAi pathway in mammalian cells.In this study,we uncovered that ER-DRI and Enoxacin drug combination can facilitate ER-DRI antiviral activity to inhibit enterovirus replication.In mammals,Dicer splice long dsRNA into 21 nt siRNA and loaded into RISC with the help of TRBP protein.Enoxacin enhance the combination of vsiRNA and TRBP protein so that improve the vsiRNAs loading into RISC complex to further inhibit virus replication.Taken together,we find that Enoxacin and ER-DRI drug combination can inhibit enterovirus replication through mammalian RNAi pathway.Macrocyclic molecule CB[7] can inhibit a wide range of RNA virus through sequestering spermine in cells.