Inhibition of norovirus replication by morpholino oligomers targeting the 5'-end of the genome.
Noroviruses are an important cause of non-bacterial epidemic gastroenteritis, but no specific antiviral therapies are available. We investigated the inhibitory effect of phosphorodiamidiate morpholino oligomers (PMOs) targeted against norovirus sequences. A panel of peptide-conjugated PMOs (PPMOs) specific for the murine norovirus (MNV) genome was developed, and two PPMO compounds directed against the first AUG of the ORF1 coding sequence near the 5'-end of the genome proved effective in inhibiting MNV replication in cells. A consensus PPMO (designated Noro 1.1), designed to target the corresponding region of several diverse human norovirus genotypes, decreased the efficiency of protein translation in a cell-free luciferase reporter assay and inhibited Norwalk virus protein expression in replicon-bearing cells. Our data suggest that PPMOs directed against the relatively conserved 5'-end of the norovirus genome may show broad antiviral activity against this genetically diverse group of viruses.
Bok
Karin
K
Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, DHHS, 50 South Drive, Bldg. 50, Room 6316, Bethesda, MD 20892, USA. bokk@niaid.nih.gov
Cavanaugh
Victoria J
VJ
Matson
David O
DO
González-Molleda
Lorenzo
L
Chang
Kyeong-Ok
KO
Zintz
Carmelann
C
Smith
Alvin W
AW
Iversen
Patrick
P
Green
Kim Y
KY
Campbell
Ann E
AE
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D002460:Cell Line; D006801:Humans; D051379:Mice; D009025:Morpholines / Q000494:pharmacology*; D029322:Norovirus / Q000187:drug effects*; D014176:Protein Biosynthesis / Q000187:drug effects; D012367:RNA, Viral / Q000378:metabolism*; D014779:Virus Replication / Q000187:drug effects*
D000998:Antiviral Agents; D009025:Morpholines; D012367:RNA, Viral
N Engl J Med. 1977 Jul 14;297(2):86-9
405590
J Virol. 2007 Nov;81(22):12111-8
17855555
Nucleic Acids Res. 2008 May;36(8):2530-46
18319285
J Virol. 2007 Nov;81(21):11669-80
17728223
Am J Vet Res. 2008 Jan;69(1):23-32
18167083
Biochim Biophys Acta. 1999 Dec 10;1489(1):141-58
10807004
Lancet. 2004 Feb 28;363(9410):671-2
15001320
Virology. 2006 Mar 15;346(2):312-23
16343580
Curr Opin Mol Ther. 2002 Apr;4(2):177-84
12044040
Proc Natl Acad Sci U S A. 2007 Jun 26;104(26):11050-5
17581883
Infect Genet Evol. 2005 Apr;5(3):281-90
15737920
J Gen Virol. 2007 Aug;88(Pt 8):2091-2100
17622609
J Virol. 2006 Jun;80(11):5104-12
16698991
J Med Virol. 2001 Dec;65(4):671-80
11745930
Antimicrob Agents Chemother. 2006 Nov;50(11):3724-33
16966399
J Infect Dis. 2000 May;181 Suppl 2:S254-61
10804134
Virology. 2006 Sep 30;353(2):463-73
16843517
Methods Enzymol. 2000;313:135-43
10595352
Bioconjug Chem. 2004 Mar-Apr;15(2):290-9
15025524
Zhonghua Yi Xue Za Zhi. 1999 Nov;79(11):857-9
11715493
J Virol. 2007 Apr;81(7):3251-63
17229692
J Infect Dis. 2000 May;181 Suppl 2:S367-73
10804150
Nat Med. 2003 May;9(5):548-53
12692541
J Virol. 2006 Aug;80(16):7816-31
16873239
J Virol. 2003 Nov;77(21):11603-15
14557646
PLoS Biol. 2004 Dec;2(12):e432
15562321
Antisense Nucleic Acid Drug Dev. 1997 Jun;7(3):151-7
9212905
Antimicrob Agents Chemother. 2001 Apr;45(4):1043-52
11257014
J Virol. 2007 Jun;81(11):5637-48
17344287
J Virol. 2007 Oct;81(19):10460-73
17652401
Antimicrob Agents Chemother. 2007 Jul;51(7):2470-82
17485503
J Virol. 2005 Aug;79(15):9665-76
16014928
Antiviral Res. 2008 Feb;77(2):95-107
17959259
Antisense Nucleic Acid Drug Dev. 2001 Oct;11(5):317-25
11763348
J Control Release. 2006 Dec 1;116(3):304-13
17097177
J Clin Microbiol. 2006 Feb;44(2):327-33
16455879