Increased stability and antiviral activity of 2′‐<i>O</i>‐phosphoglyceryl derivatives of (2′‐5′)oligo(adenylate)

Bayard, Bernard; Bisbal, Catherine; Silhol, Michelle; Cnockaert, Joël J.; Huez, Georges; Lebleu, Bernard

doi:10.1111/j.1432-1033.1984.tb08284.x

Cited by 43 publications

(23 citation statements)

References 33 publications

(19 reference statements)

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“…This is at least 20-fold lower than the concentration of natural 2-5A in IFNtreated EMC virus-infected L cells [6]. These results confirm previous observations that VSV growth is sensitive to inhibition by natural 2-5A [39,40] and 2'-0-phosphoglyceryl derivatives of 2-5A [41], although the 2-5A system does not appear to be activated in intact cells [42,43].…”

Section: Concentration Andisupporting

confidence: 87%

“…Upon microinjection of natural 2-SA complete inhibition of VSV growth was achieved at 100 nM-1 PM 2-5A inside the cell (not shown) [39,41]. The work presented here shows that in intact cells the tailed analogs are at least 100-fold more active than natural 2-5A.…”

Section: Concentration Andimentioning

confidence: 78%

“…The work presented here shows that in intact cells the tailed analogs are at least 100-fold more active than natural 2-5A. Moreover, the activity of the 2-5A hexylmorpholine analog towards VSV is at least IOOO-fold higher than that obtained with the phosphoglyceryl derivatives of 2-5A 1411, although the two analogs have comparable activity and stability in an in vitro assay [36,41].…”

Section: Concentration Andimentioning

confidence: 98%

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Antiviral activity of a chemically stabilized 2‐5A analog upon microinjection into HeLa cells

et al. 1986

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2‐5A[ppp(A2'p) n 5'A] has been implicated as a mediator in the antiviral action of interferon. Its direct evaluation as an indicator of virus replication is hampered by two limitations: its inability to penetrate intact cells, and its rapid intracellular degradation by (2'–5')phosphodiesterase. These problems could be overcome by using a microinjection technique whereby a phosphodiesterase‐resistant analog of 2‐A, in which the 2'‐terminals adenosine residue is replaced by 2‐(9‐adenyl)‐6‐hydroxy‐methyl‐4‐hexylmorpholine, was injected into individual HeLa cells before infection with mengovirus or vesicular stomatitis virus (VSV). This comparative assay with two representatives of different virus classes in a single experimental system pointed to the high sensitivity of VSV to inhibition by 2‐5A oligonucleotides, in contrast with the low sensitivity of mengovirus. Microinjection of the hexylmorpholine 2‐5A analog led to a much greater reduction in mengovirus yield than did microinjection of 2‐5A itself.

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Section: Concentration Andisupporting

confidence: 87%

Section: Concentration Andimentioning

confidence: 78%

Section: Concentration Andimentioning

confidence: 98%

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Antiviral activity of a chemically stabilized 2‐5A analog upon microinjection into HeLa cells

et al. 1986

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“…32 P]pCp probe was oxidized at its 3Ј end (21). This modified probe can be covalently linked to amine groups on RNase L and allows analysis by denaturing gel electrophoresis as initially described by Wreschner et al (22) with our modifications (23).…”

Section: Cell Extracts and Isolation Of H9mentioning

confidence: 99%

The 2–5A/RNase L/RNase L Inhibitor (RNI) Pathway Regulates Mitochondrial mRNAs Stability in Interferon α-treated H9 Cells

Roy¹,

Bisbal²,

Silhol³

et al. 2001

Journal of Biological Chemistry

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Interferon ␣ (IFN␣) belongs to a cytokine family that exhibits antiviral properties, immuno-modulating effects, and antiproliferative activity on normal and neoplasic cells in vitro and in vivo. IFN␣ exerts antitumor action by inducing direct cytotoxicity against tumor cells. This toxicity is at least partly due to induction of apoptosis. Although the molecular basis of the inhibition of cell growth by IFN␣ is only partially understood, there is a direct correlation between the sensitivity of cells to the antiproliferative action of IFN␣ and the down-regulation of their mitochondrial mRNAs. Here, we studied the role of the 2-5A/RNase L system and its inhibitor RLI in this regulation of the mitochondrial mRNAs by IFN␣. We found that a fraction of cellular RNase L and RLI is localized in the mitochondria. Thus, we down-regulated RNase L activity in human H9 cells by stably transfecting (i) RNase L antisense cDNA or (ii) RLI sense cDNA constructions. In contrast to control cells, no post-transcriptional down-regulation of mitochondrial mRNAs and no cell growth inhibition were observed after IFN␣ treatment in these transfectants. These results demonstrate that IFN␣ exerts its antiproliferative effect on H9 cells at least in part via the degradation of mitochondrial mRNAs by RNase L. Interferons (IFNs)1 belong to a family of cytokines produced and secreted by mammalian cells in response to various stimuli. Although originally discovered due to their participation in cellular defense against viral infection (1), IFNs are also known to modulate immune responses as well as control various cellular functions by altering the transcription of a large family of genes involved in cell proliferation and differentiation (2, 3).IFNs are negative regulators of cell proliferation through induction of cell cycle arrest and apoptosis, which has also been suggested to be of central importance in IFN antitumor action. IFN␣ (type I family) has emerged as a tumor suppressor protein. A number of clinical trials were thus carried out in cancer therapy with IFN␣ alone or in combination with other negative regulators of cell proliferation (4, 5). It has been shown to be effective against hematological malignancies including hairy cell leukemia, chronic myelogenous leukemia, and cutaneous T-cell lymphoma (6). IFN␣ has been used successfully in cancer therapy, but development of resistance to IFN␣ therapy has often been observed in patients. Although the molecular basis of the inhibition of cell growth by IFN␣ is partially understood, there is a correlation between the sensitivity of cells to the antiproliferative action of IFN␣ and the down-regulation of their mitochondrial mRNAs and the impairment of mitochondrial function upon IFN␣ treatment (7,8).In this work, we have studied the role of one of the enzymatic pathways induced by IFN␣, the 2-5A/RNase L pathway, in the regulation of mitochondrial mRNAs. The 2-5A/RNase L pathway is an RNA degradation pathway (9). IFN␣ induces the expression of 2-5A synthetase(s) which, upon activation by dou...

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“…[9] Thus far, a number of 2-5A analogues with modification of the bases, riboses, internucleotide linkages, and a 5'-phosphoryl group have been synthesized to test RNase L activating activity in vitro. [1,[10][11][12][13][14][15][16] However, no intracellular-effective 2-5A analogue with both sufficient RNase L agonistic activity and high resistance against enzymatic degradation has been reported except for fully phosphorothioated 2-5A. [17] In many cases, the phosphorothioate modification of oligonucleotides seem to bind nonspecifically to protein.…”

mentioning

confidence: 99%

Biologically Stable 2‐5A Analogues containing 3′‐O,4′‐C‐bridged Adenosine as Potent RNase L Agonists

et al. 2007

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Increased stability and antiviral activity of 2′‐O‐phosphoglyceryl derivatives of (2′‐5′)oligo(adenylate)

Cited by 43 publications

References 33 publications

Antiviral activity of a chemically stabilized 2‐5A analog upon microinjection into HeLa cells

Antiviral activity of a chemically stabilized 2‐5A analog upon microinjection into HeLa cells

The 2–5A/RNase L/RNase L Inhibitor (RNI) Pathway Regulates Mitochondrial mRNAs Stability in Interferon α-treated H9 Cells

Biologically Stable 2‐5A Analogues containing 3′‐O,4′‐C‐bridged Adenosine as Potent RNase L Agonists

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