Peptide-Mediated Interference of PB2-eIF4G1 Interaction Inhibits Influenza A Viruses' Replication in Vitro and in Vivo.
Influenza viruses are obligate parasites that hijack the host cellular system. Previous results have shown that the influenza virus PB2 subunit confers a dependence of host eukaryotic translation initiation factor 4-γ 1 (eIF4G1) for viral mRNA translation. Here, we demonstrated that peptide-mediated interference of the PB2-eIF4G1 interaction inhibited virus replication in vitro and in vivo. Remarkably, intranasal administration of the peptide provided 100% protection against lethal challenges of influenza A viruses in BALB/c mice, including H1N1, H5N1, and H7N9 influenza virus subtypes. Mapping of the PB2 protein indicated that the eIF4G1 binding sites resided within the PB2 cap-binding domain. Virtual docking analysis suggested that the inhibitory peptide associated with the conserved amino acid residues that were essential to PB2 cap-binding activity. Overall, our results identified the PB2-eIF4G1 interactive site as a druggable target for influenza therapeutics.
Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong , Hong Kong SAR, China.
Shuofeng
S
Yuan
Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong , Hong Kong SAR, China.
Hin
H
Chu
Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong , Hong Kong SAR, China.
Jiahui
J
Ye
Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong , Hong Kong SAR, China.
Meng
M
Hu
School of Biological Sciences, Faculty of Science, The University of Hong Kong , Hong Kong SAR, China.
Kailash
K
Singh
School of Biological Sciences, Faculty of Science, The University of Hong Kong , Hong Kong SAR, China.
Billy K C
BK
Chow
Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong , Hong Kong SAR, China.
Jie
J
Zhou
Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong , Hong Kong SAR, China.
Bo-Jian
BJ
Zheng
D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D039603:Eukaryotic Initiation Factor-4G / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D053124:Influenza A Virus, H5N1 Subtype / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D064766:Influenza A Virus, H7N9 Subtype / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D007251:Influenza, Human / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000821:virology; D051379:Mice; D008807:Mice, Inbred BALB C; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding; D000072417:Protein Domains; D012324:RNA-Dependent RNA Polymerase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014764:Viral Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
D000998:Antiviral Agents; C113920:EIF4G1 protein, human; D039603:Eukaryotic Initiation Factor-4G; C057027:PB2 protein, Influenzavirus A; D010455:Peptides; D014764:Viral Proteins; D012324:RNA-Dependent RNA Polymerase
PB2; Tat; antiviral peptide; eIF4G1; host−virus interaction; influenza virus