Adenosine analogs inhibit the guanine‐7‐methylation of mRNA cap structures

Oxenrider, Keith A.; Bu, Guojun; Sitz, Thomas O.

doi:10.1016/0014-5793(93)81307-l

Cited by 12 publications

(4 citation statements)

References 14 publications

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“…Various adenosine analogues have been used previously to indirectly inhibit the in vivo formation of the mRNA cap structure by raising the cellular S-adenosylhomocysteine (SAH) levels through the inhibition of S-adenosylhomocysteine hydrolase (27). In contrast, our study demonstrates for the first time that a nucleoside analogue can be recognized directly by a viral capping enzyme and transferred to an acceptor RNA molecule.…”

Section: Discussionmentioning

confidence: 41%

The Broad Spectrum Antiviral Nucleoside Ribavirin as a Substrate for a Viral RNA Capping Enzyme

Bougie

Bisaillon

2004

Journal of Biological Chemistry

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The broad spectrum antiviral nucleoside ribavirin displays activity against a variety of RNA and DNA viruses. A number of possible mechanisms have been proposed during the past 30 years to account for the antiviral activity of ribavirin, including the possibility that ribavirin might have a negative effect on the synthesis of the RNA cap structure of viral RNA transcripts. In the present study, we investigated the possibility that ribavirin can directly serve as a substrate for the vaccinia virus RNA capping enzyme. We demonstrate that ribavirin triphosphate can be used as a substrate by the capping enzyme and can form a covalent ribavirin monophosphate-enzyme intermediate reminiscent of the classical GMP-enzyme intermediate. Furthermore, our data indicate that ribavirin monophosphate can be transferred to the diphosphate end of an RNA transcript to form the unusual RpppN structure. Finally, we provide evidence that RNA transcripts that possess ribavirin as the blocking nucleoside are more stable than unblocked transcripts. However, in vitro translation assays indicate that RNA transcripts blocked with ribavirin are not translated efficiently. Our study provides the first biochemical evidences that ribavirin can directly interact with a viral capping enzyme. The ability of a purified RNA capping enzyme to utilize ribavirin as a substrate has not been previously documented and has implications for our understanding of the catalytic mechanisms of RNA capping enzymes. The biological implications of these findings for the proposed ribavirin-mediated inhibition of capping are discussed.

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Section: Discussionmentioning

confidence: 41%

The Broad Spectrum Antiviral Nucleoside Ribavirin as a Substrate for a Viral RNA Capping Enzyme

Bougie

Bisaillon

2004

Journal of Biological Chemistry

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“…Inhibition of SAH hydrolase increases the intracellular SAH/ SAM ratio, resulting in feedback inhibition of methylation (Cools and De Clercq, 1990). The antiviral activity of SAH hydrolase inhibitors has been attributed to diminished methylation of the 5% cap of viral messenger RNA by the viral (guanine-7-)methyltransferase, which impairs translation of viral transcripts (Oxenrider et al, 1993).…”

Section: Introductionmentioning

confidence: 99%

3-Deazaneplanocin A induces massively increased interferon-α production in Ebola virus-infected mice

et al. 2002

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3-Deazaneplanocin A, an analog of adenosine, is a potent inhibitor of Ebola virus replication. A single dose early in infection prevents illness and death in Ebola virus-infected mice. The ability of this and similar compounds to block both RNA and DNA viruses has been attributed to the inhibition of a cellular enzyme, S-adenosylhomocysteine hydrolase (SAH), indirectly resulting in reduced methylation of the 5% cap of viral messenger RNA. However, we found that the protective effect of the drug resulted from massively increased production of interferon-a in Ebola-infected, but not uninfected mice. Peak interferon levels increased with the extent of disease at the time of treatment, indicating that production was boosted only in virus-infected cells. Ebola virus has been shown to suppress innate antiviral mechanisms of the type I interferon response. 3-Deazaneplanocin A appears to reverse such suppression, restricting viral dissemination. Further development should focus on identifying adenosine analogues that produce a similar effect in Ebola virus-infected primates. Published by Elsevier Science B.V.

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“…Among the most significant of these methylase reactions are those responsible for the capping of mRNA at the N-7 of the terminal 5‘-5‘-guanosine triphosphate and the O-2‘ of the neighboring adenosines . In searching for new antiviral agents whose mode of action is inhibition of viral mRNA methyltransferases, analogues of AdoMet acting as cofactor-based inhibitors are being evaluated in our laboratory. In this direction, because of our work and others that have found carbocyclic nucleosides to be potent inhibitors of AdoMet-mediated methylations, including those of viral mRNA, we became interested in carbocyclic AdoMet.…”

mentioning

confidence: 99%

Preparation of Carbocyclic S-Adenosylazamethionine Accompanied by a Practical Synthesis of (−)-Aristeromycin

Yang

Schneller

2004

J. Org. Chem.

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For the preparation of a carbocyclic nitrogen analogue of S-adenosylmethionine (carba-AdoazaMet, 4), a practical synthesis of (-)-aristeromycin (7) has been developed using variations of literature procedures. This approach called for a stereospecific synthesis of (3aR,6aR)-2,2-dimethyl-3a,6a-dihydrocyclopenta[1,3]dioxol-4-one ((4R, 5R)-4,5-O-isopropylidene-2-cyclopentenone) (8), which was achieved by modifying reported procedures from D-(-)-ribose.

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Adenosine analogs inhibit the guanine‐7‐methylation of mRNA cap structures

Cited by 12 publications

References 14 publications

The Broad Spectrum Antiviral Nucleoside Ribavirin as a Substrate for a Viral RNA Capping Enzyme

The Broad Spectrum Antiviral Nucleoside Ribavirin as a Substrate for a Viral RNA Capping Enzyme

3-Deazaneplanocin A induces massively increased interferon-α production in Ebola virus-infected mice

Preparation of Carbocyclic S-Adenosylazamethionine Accompanied by a Practical Synthesis of (−)-Aristeromycin

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