tetano
Editor, Senior Moderator
J Virol. 2013 Feb 13. [Epub ahead of print]
Nucleozin targets cytoplasmic trafficking of vRNP-Rab11 complexes in influenza A virus infection.
Amorim MJ, Kao R, Digard P.
Source
Division of Virology, Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QP, United Kingdom.
Abstract
Novel antivirals are needed to supplement existing control strategies for influenza A virus (IAV). A promising new class of drug, exemplified by the compound nucleozin, has recently been identified that targets the viral nucleoprotein (NP). These inhibitors are thought to act as 'molecular staples' that stabilise interactions between NP monomers, promoting the formation of non-functional aggregates. Here we detail the inhibitory mechanism of nucleozin, finding that the drug has both early- and late-acting effects on the IAV lifecycle. When present at the start of infection, it inhibited viral RNA and protein synthesis. However, when added at later time points, it still potently blocked the production of infectious progeny but without affecting viral macromolecular synthesis. Instead, nucleozin blocked the cytoplasmic trafficking of RNPs that had undergone nuclear export, promoting the formation of large perinuclear aggregates of RNPs along with cellular Rab11. This effect led to the production of much reduced amounts of often markedly smaller virus particles. We conclude that the primary target of nucleozin is the viral RNP, not NP and this work also provides proof of principle that IAV replication can be effectively inhibited by blocking cytoplasmic trafficking of the viral genome.
PMID:
23408618
[PubMed - as supplied by publisher]
http://www.ncbi.nlm.nih.gov/pubmed/23408618
Nucleozin targets cytoplasmic trafficking of vRNP-Rab11 complexes in influenza A virus infection.
Amorim MJ, Kao R, Digard P.
Source
Division of Virology, Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QP, United Kingdom.
Abstract
Novel antivirals are needed to supplement existing control strategies for influenza A virus (IAV). A promising new class of drug, exemplified by the compound nucleozin, has recently been identified that targets the viral nucleoprotein (NP). These inhibitors are thought to act as 'molecular staples' that stabilise interactions between NP monomers, promoting the formation of non-functional aggregates. Here we detail the inhibitory mechanism of nucleozin, finding that the drug has both early- and late-acting effects on the IAV lifecycle. When present at the start of infection, it inhibited viral RNA and protein synthesis. However, when added at later time points, it still potently blocked the production of infectious progeny but without affecting viral macromolecular synthesis. Instead, nucleozin blocked the cytoplasmic trafficking of RNPs that had undergone nuclear export, promoting the formation of large perinuclear aggregates of RNPs along with cellular Rab11. This effect led to the production of much reduced amounts of often markedly smaller virus particles. We conclude that the primary target of nucleozin is the viral RNP, not NP and this work also provides proof of principle that IAV replication can be effectively inhibited by blocking cytoplasmic trafficking of the viral genome.
PMID:
23408618
[PubMed - as supplied by publisher]
http://www.ncbi.nlm.nih.gov/pubmed/23408618