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rdf:type |
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lifeskim:mentions |
umls-concept:C0007585,
umls-concept:C0021467,
umls-concept:C0021469,
umls-concept:C0029341,
umls-concept:C0030946,
umls-concept:C0042769,
umls-concept:C0086418,
umls-concept:C0458827,
umls-concept:C0599219,
umls-concept:C0599894,
umls-concept:C1336641,
umls-concept:C1881903
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pubmed:issue |
4
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pubmed:dateCreated |
2011-1-21
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pubmed:abstractText |
Influenza A viruses constitute a major and ongoing global public health concern. Current antiviral strategies target viral gene products; however, the emergence of drug-resistant viruses highlights the need for novel antiviral approaches. Cleavage of the influenza virus hemagglutinin (HA) by host cell proteases is crucial for viral infectivity and therefore presents a potential drug target. Peptide-conjugated phosphorodiamidate morpholino oligomers (PPMO) are single-stranded-DNA-like antisense agents that readily enter cells and can act as antisense agents by sterically blocking cRNA. Here, we evaluated the effect of PPMO targeted to regions of the pre-mRNA or mRNA of the HA-cleaving protease TMPRSS2 on proteolytic activation and spread of influenza viruses in human Calu-3 airway epithelial cells. We found that treatment of cells with a PPMO (T-ex5) designed to interfere with TMPRSS2 pre-mRNA splicing resulted in TMPRSS2 mRNA lacking exon 5 and consequently the expression of a truncated and enzymatically inactive form of TMPRSS2. Altered splicing of TMPRSS2 mRNA by the T-ex5 PPMO prevented HA cleavage in different human seasonal and pandemic influenza A viruses and suppressed viral titers by 2 to 3 log(10) units, strongly suggesting that TMPRSS2 is responsible for HA cleavage in Calu-3 airway cells. The data indicate that PPMO provide a useful reagent for investigating HA-activating proteases and may represent a promising strategy for the development of novel therapeutics to address influenza infections.
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pubmed:commentsCorrections |
http://linkedlifedata.com/resource/pubmed/commentcorrection/21123387-10329563,
http://linkedlifedata.com/resource/pubmed/commentcorrection/21123387-10355827,
http://linkedlifedata.com/resource/pubmed/commentcorrection/21123387-10807004,
http://linkedlifedata.com/resource/pubmed/commentcorrection/21123387-10966468,
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http://linkedlifedata.com/resource/pubmed/commentcorrection/21123387-19158246,
http://linkedlifedata.com/resource/pubmed/commentcorrection/21123387-19357398,
http://linkedlifedata.com/resource/pubmed/commentcorrection/21123387-19487698,
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http://linkedlifedata.com/resource/pubmed/commentcorrection/21123387-20219906,
http://linkedlifedata.com/resource/pubmed/commentcorrection/21123387-20237084,
http://linkedlifedata.com/resource/pubmed/commentcorrection/21123387-20631123,
http://linkedlifedata.com/resource/pubmed/commentcorrection/21123387-7023022,
http://linkedlifedata.com/resource/pubmed/commentcorrection/21123387-8057485,
http://linkedlifedata.com/resource/pubmed/commentcorrection/21123387-8162439,
http://linkedlifedata.com/resource/pubmed/commentcorrection/21123387-9012862,
http://linkedlifedata.com/resource/pubmed/commentcorrection/21123387-9212905,
http://linkedlifedata.com/resource/pubmed/commentcorrection/21123387-9212909,
http://linkedlifedata.com/resource/pubmed/commentcorrection/21123387-9325052
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Hemagglutinin Glycoproteins...,
http://linkedlifedata.com/resource/pubmed/chemical/Metalloendopeptidases,
http://linkedlifedata.com/resource/pubmed/chemical/Morpholines,
http://linkedlifedata.com/resource/pubmed/chemical/Morpholinos,
http://linkedlifedata.com/resource/pubmed/chemical/RNA, Messenger,
http://linkedlifedata.com/resource/pubmed/chemical/RNA Precursors,
http://linkedlifedata.com/resource/pubmed/chemical/Serine Endopeptidases,
http://linkedlifedata.com/resource/pubmed/chemical/TMPRSS2 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/hemagglutinin-protease
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pubmed:status |
MEDLINE
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pubmed:month |
Feb
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pubmed:issn |
1098-5514
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pubmed:author |
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pubmed:issnType |
Electronic
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pubmed:volume |
85
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
1554-62
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pubmed:dateRevised |
2011-11-17
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pubmed:meshHeading |
pubmed-meshheading:21123387-Humans,
pubmed-meshheading:21123387-Animals,
pubmed-meshheading:21123387-Bronchi,
pubmed-meshheading:21123387-Dogs,
pubmed-meshheading:21123387-Morpholines,
pubmed-meshheading:21123387-Epithelial Cells,
pubmed-meshheading:21123387-Chick Embryo,
pubmed-meshheading:21123387-Influenza A virus,
pubmed-meshheading:21123387-Metalloendopeptidases,
pubmed-meshheading:21123387-Cells, Cultured,
pubmed-meshheading:21123387-RNA, Messenger,
pubmed-meshheading:21123387-Cell Line,
pubmed-meshheading:21123387-Serine Endopeptidases,
pubmed-meshheading:21123387-Hemagglutinin Glycoproteins, Influenza Virus,
pubmed-meshheading:21123387-RNA Precursors
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