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Titolo:
2-5A-DNA conjugate inhibition of respiratory syncytial virus replication: effects of oligonucleotide structure modifications and RNA target site selection
Autore:
Barnard, DL; Sidwell, RW; Xiao, W; Player, MR; Adah, SA; Torrence, PF;
Indirizzi:
NIDDKD, Sect Biomed Chem, Med Chem Lab, NIH, Bethesda, MD 20892 USA NIDDKD Bethesda MD USA 20892 m, Med Chem Lab, NIH, Bethesda, MD 20892 USA Utah State Univ, Inst Antiviral Res, Logan, UT 84322 USA Utah State Univ Logan UT USA 84322 nst Antiviral Res, Logan, UT 84322 USA
Titolo Testata:
ANTIVIRAL RESEARCH
fascicolo: 3, volume: 41, anno: 1999,
pagine: 119 - 134
SICI:
0166-3542(199904)41:3<119:2CIORS>2.0.ZU;2-#
Fonte:
ISI
Lingua:
ENG
Soggetto:
HUMAN-IMMUNODEFICIENCY-VIRUS; HUMAN CYTOMEGALOVIRUS; ANTIVIRAL ACTIVITY; PHOSPHOROTHIOATE OLIGONUCLEOTIDE; 2-5A-ANTISENSE CHIMERAS; ANTISENSE CHIMERAS; COMPLEMENTARY; OLIGODEOXYNUCLEOTIDES; DEGRADATION; CELLS;
Keywords:
respiratory syncytial virus; oligonucleotides; antiviral; 2-5A-antisense; RNase L;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
60
Recensione:
Indirizzi per estratti:
Indirizzo: Torrence, PF NIDDKD,20892 Biomed Chem, Med Chem Lab, NIH, Bldg 8 Rm B2A02,Bethesda, MD NIDDKD Bldg 8 Rm B2A02 Bethesda MD USA 20892 02, Bethesda, MD
Citazione:
D.L. Barnard et al., "2-5A-DNA conjugate inhibition of respiratory syncytial virus replication: effects of oligonucleotide structure modifications and RNA target site selection", ANTIVIR RES, 41(3), 1999, pp. 119-134

Abstract

To define more fully the conditions for 2-5A-antisense inhibition of respiratory syncytial virus (RSV), relationships between 2-5A antisense oligonucleotide structure and the choice of RNA target sites to inhibition of RSV replication have been explored. The lead 2-5A-antisense chimera for this study was the previously reported NIH8281 that targets the RSV M2 RNA. We haveconfirmed and extended the earlier study by showing that NIH8281 inhibitedRSV strain A2 replication in a variety of antiviral assays, including virus yield reduction assays performed in monkey (EC90 = 0.02 mu M) and human cells (EC90 = 1 mu M). This 2-5A-antisense chimera also inhibited other A strains, B strains and bovine RSV in cytopathic effect inhibition and NeutralRed Assays (EC50 values = 0.1-1.6 mu M). The 2'-O-methylation modificationof NIH8281 to increase affinity for the complementary RNA and provide nuclease resistance, the introduction of phosphothioate groups in the antisensebackbone to enhance resistance to exo- and endonucleases, and the additionof cholesterol to the 3'-terminus of the antisense oligonucleotide to increase cellular uptake, all resulted in loss of activity. Of the antisense chimeras targeting other RSV mRNAs (NS1, NS2, P, M. G, F, and L), only those complementary to L mRNA were inhibitory. These results suggest that lower abundance mRNAs may be the best targets for 2-5A-antisense; moreover, the active 2-5A antisense chimeras in this study may serve as useful guides for the development of compounds with improved stability, uptake and anti-RSV activity. (C) 1999 Elsevier Science B.V. All rights reserved.

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Documento generato il 03/07/20 alle ore 22:07:39