Inhibition of replication and expression of human T-cell lymphotropic virus type III in cultured cells by exogenous synthetic oligonucleotides complementary to viral RNA.

Zamecnik, Paul C.; Goodchild, John; Taguchi, Yoshi; Sarin, Prem S.

doi:10.1073/pnas.83.12.4143

Cited by 367 publications

(143 citation statements)

References 33 publications

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“…Moreover, our recovery of the oligodeoxynucleotide in vivo is similar to that reported in cell culture system. In culture systems using cells supplemented with medium and heat-inactivated serum, about 1 to 2% of an added unmodified phosphodiester oligodeoxynucleotide can be internalized within 4 hours [37], and 25% was degraded after 24 hours [54,55]. The delay by 2 hours in our study could be due to a difference between the uptake by cells in a monolayer cell culture system and that in the in vivo multilayer cell system.…”

mentioning

confidence: 64%

Suppression of ischemia‐induced fos expression and AP‐1 activity by an antisense oligodeoxynucleotide to c‐fos mRNA

Liu

Salminen

et al. 1994

Annals of Neurology

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Activation of c-fos, an immediate early gene, and the subsequent expression of the Fos protein have been noted following focal cerebral ischemia. Fos and Jun form a heterodimer as activator protein 1 (AP-1), which transregulates the expression of several genes. To study the postischemic events related to c-fos expression, we suppressed the expression of c-fos by intraventricular infusion of an antisense Oligodeoxynucleotide (anti-rncfosr 115 ) of c-fos mRNA. The effectiveness of antirncfosr 115 was confirmed first by its capability to block in vitro c-fos mRNA translation. In vivo, after intraventricular infusion of 32 P-labeled anti-rncfosr 115 , the oligodeoxynucleotide was internalized within 6 hours and detectable also in the nucleic acids fraction up to 41 hours. Treatment of the recovered nucleic acids with RNase H separated the labeled Oligodeoxynucleotide from the nucleic acid fraction, indicating an association of the antisense Oligodeoxynucleotide and cellular RNA after uptake. When focal cerebral ischemia was induced 16 hours after the infusion of antirncfosr 115 , the postischemic increase in Fos expression and AP-1 binding activity were suppressed. Specificity of the effect of anti-rncfosr 115 was suggested by its failure to suppress the DNA binding activity of nuclear cyclic AMP response elements. These results support the hypothesis that increased AP-1 binding activity following focal cerebral ischemia is dependent on Fos expression and can be inhibited in vivo by antisense c-fos oligodeoxynucleotides.The molecular events of brain adaptation to injury that may underlie functional recovery after stroke remain largely undefined. Recent observations of altered gene expression in ischemic brain using animal stroke models have opened new avenues for exploration of the biochemical cascades after stroke [1][2][3][4][5][6][7][8][9][10][11]. These postischemic events include an increase in extracellular excitatory amino acid neurotransmitters such as glutamate. Glutamate receptor-mediated activation of phospholipases and protein kinases results in the alteration of nuclear regulatory processes, including the expression of immediate early genes such as c-fos, junB, and c-jun [5,12]. The Fos, Jun, and JunB proteins have been shown to form activator protein 1 (AP-1) through a conserved dimerization domain, i.e., the leucine zipper [13]. Transcription regulator AP-1 protein binds a specific DNA motif and is believed to transactivate the expression of a number of late effector genes [14][15][16][17][18][19]. In the ischemic brain, we have previously demonstrated an increase in AP-1 binding activity [9]. A number of genes that bear neurotrophic properties may be regulated by transcription regulator AP-1. These genes, such as heat shock protein [1,4,[19][20][21][22], amyloid [23], neurotrophins [7], and protein tyrosine kinase receptor trkB [24], have been shown to be induced following cerebral ischemia. The causal relationship between the Fos/Jun-AP-1 cascade and the subsequent expression of the late e...

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confidence: 64%

Suppression of ischemia‐induced fos expression and AP‐1 activity by an antisense oligodeoxynucleotide to c‐fos mRNA

Liu

Salminen

et al. 1994

Annals of Neurology

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“…Subsequently, antisense oligonucleotides have been used against a wide range of different types of viruses, including the negative-strand RNA viruses such as rabies virus (5) and influenza virus (6), positive-strand RNA viruses such as dengue virus (7), DNA viruses including hepatitis B (8) and herpes simplex virus type 1 (9), and the retrovirus HIV-1 (10,11). Despite encouraging results, significant challenges remain in the development of antisense oligonucleotides as antiviral agents.…”

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confidence: 99%

Targeting RNA decay with 2′,5′ oligoadenylate-antisense in respiratory syncytial virus-infected cells

Cirino

Xiao

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

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Treatment of human cells with 2 ,5 oligoadenylate covalently linked to antisense (2-5A-antisense) results in the selective cleavage of targeted RNA species by 2-5A-dependent RNase L. Here we show that 2-5A-antisense containing stabilizing modifications at both termini are effective in suppressing the replication of respiratory syncytial virus (RSV) in human tracheal epithelial cells. The affinity of 2-5A-antisense for different regions in the RSV M2 and L mRNAs was predicted from a computer-generated model of the RNA secondary structure. The most potent 2-5A-antisense molecule caused a highly effective, dose-dependent suppression of RSV yields when added to previously infected cells. In contrast, control oligonucleotides, including an inactive dimeric form of 2-5A linked to antisense, 2-5A linked to a randomized sequence of nucleotides, and antisense molecules lacking 2-5A, had minimal effects on virus replication. The specificity of this approach was shown by reverse transcriptase-coupled PCR analysis of RSV M2, P, and N mRNA and of cellular glyceraldehyde-3-phosphate dehydrogenase mRNA. The RSV M2 mRNA amounts were depleted after treating RSV-infected cells with 2-5A-antisense targeted to this mRNA, whereas the amounts of the other RNA species were unchanged. These studies demonstrate that 2 ,5 oligoadenylate covalently linked to antisense (2-5A-antisense) can effectively suppress RSV replication by directing the cellular RNase L to selectively degrade an essential viral mRNA.Respiratory syncytial virus (RSV), a nonsegmented, negativestrand RNA virus in the pneumovirus genus of Paramyxoviridae, is a major cause of lower respiratory disease, resulting in 90,000 hospitalizations and 4500 deaths per year in infants and young children in the United States (1). Of growing concern are outbreaks of RSV within institutionalized elderly (2) and immunodeficient (1) adults. There is only one approved anti-RSV compound, ribavirin, which reduces virus shedding in infected children, but has no effect on mortality or duration of hospitalization (3). In the search for alternative antiviral strategies, we have investigated the potential of novel chimeric antisense molecules, 2-5A-antisense, in the control of RSV infections.Zamecnik and Stephenson were the first to report an antiviral effect of antisense oligonucleotides by showing that replication of the retrovirus Rous sarcoma virus could be inhibited by the addition of oligonucleotides complementary in sequence to reiterated terminal sequences of the viral 35S RNA (4). Subsequently, antisense oligonucleotides have been used against a wide range of different types of viruses, including the negative-strand RNA viruses such as rabies virus (5) and influenza virus (6), positive-strand RNA viruses such as dengue virus (7), DNA viruses including hepatitis B (8) and herpes simplex virus type 1 (9), and the retrovirus HIV-1 (10, 11). Despite encouraging results, significant challenges remain in the development of antisense oligonucleotides as antiviral agents. For instance, ...

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“…[1][2][3] Two limitations of natural DNA oligomers in these applications are their low binding affinity [2] and also their limited stability, due to cleavage by exo-and endonucleases which occur in natural systems. [4,5] We report here the construction of circular hybrid molecules which contain two oligonucleotide domains bridged by two oligoethylene glycol chains. These molecules bind with high affinity to complementary strands of RNA and DNA and display exceptional resistance to degradation by nucleases.…”

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confidence: 99%

“…[11] The primary cause of degradation of standard DNA oligomers in biological applications is a 3′-exonuclease activity found in cells. [4,5] Although present in lower activity, endonucleases are also found, which degrade DNA oligomers at internal phosphodiester bonds. [2] Attempts at cleavage of 1 and 2 by exonucleases confirm that they are completely resistant, due to their circular structures.…”

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confidence: 99%

DNA Recognition by Hybrid Oligoether–Oligodeoxynucleotide Macrocycles

Rumney

Kool

1992

Angew. Chem. Int. Ed. Engl.

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The sequence-specific binding of RNA and DNA by synthetic oligonucleotides and analogues is important as a diagnostic tool in the study of naturally ocurring polynucleotides and is the subject of intense research as a potential therapeutic strategy as well. [1][2][3] Two limitations of natural DNA oligomers in these applications are their low binding affinity [2] and also their limited stability, due to cleavage by exo-and endonucleases which occur in natural systems. [4,5] We report here the construction of circular hybrid molecules which contain two oligonucleotide domains bridged by two oligoethylene glycol chains. These molecules bind with high affinity to complementary strands of RNA and DNA and display exceptional resistance to degradation by nucleases.Oligoethylene glycol chains have been successfully used as simple linking groups which replace nucleotide units in linear oligonucleotide chains [6] and in hairpin-shaped oligonucleotides in duplexes and triplexes as well. [7] We wished to determine whether such spacers could be incorporated into circular structures and what the effect on their recognition properties and stability would be. We have previously shown that circular oligonucleotides can display very strong binding affinity [8] and high sequence selectivity [9] for singlestranded DNA and RNA by forming bimolecular triple helices. These macrocycles bind by forming bonds on two sides of a linear target strand, and their unusual recognition characteristics arise from the preorganized circular structure. [10] Examination of models [11] and published data on DNA triple helices [12] revealed that a group 19-21 Å long would be ideal for bridging the outer pyrimidine strands, and that fivebase nucleotide loops might be replaced with penta-or hexaethylene glycol chains. In addition to confirming our model for the binding, such a replacement might lead to favorable properties, such as lower cost and higher synthesis yield (by decreasing the number of nucleotide units), longer lifetimes in biological media, and possibly, improved membrane permeability (by decreasing total negative charge).The linear precursors to the compounds investigated in this study 1-3 were constructed by automated DNA synthesis methods [13] (Experimental Procedure) with the introduction of the synthetic dimethoxytrityl hexa-or pentaethylene glycol (HEG or PEG) phosphoramidites [7] at two positions. The oligomers d(A) 12 (for 1) and

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Inhibition of replication and expression of human T-cell lymphotropic virus type III in cultured cells by exogenous synthetic oligonucleotides complementary to viral RNA.

Cited by 367 publications

References 33 publications

Suppression of ischemia‐induced fos expression and AP‐1 activity by an antisense oligodeoxynucleotide to c‐fos mRNA

Suppression of ischemia‐induced fos expression and AP‐1 activity by an antisense oligodeoxynucleotide to c‐fos mRNA

Targeting RNA decay with 2′,5′ oligoadenylate-antisense in respiratory syncytial virus-infected cells

DNA Recognition by Hybrid Oligoether–Oligodeoxynucleotide Macrocycles

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