The Inhibition of Vaccinia Virus Replication by 5,6-Dichloro-1-beta-D-ribofuranosylbenzimidazole (DRB): an Effect at the Assembly Stage

Pothier, Pierre; Dru, Alfred; Beaud, Georges

doi:10.1099/0022-1317-55-1-87

Cited by 13 publications

(10 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…19 Previous reports of l-/?-D-ribofuranosylbenzimidazole nucleosides29-31 indicate that the Jy.%' coupling constants tend to be >5 Hz for such compounds and therefore cannot be used to establish anomeric configuration. We found that all nucleosides (4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23) prepared in this study possessed a Jy.% >5 Hz. However, the dethiation of 5 to give DRB (with a Jy.y of 6.3 Hz) established the /3-anomeric configuration for all nucleosides (4-23).…”

Section: Introductionmentioning

confidence: 60%

Benzimidazole Ribonucleosides: Design, Synthesis, and Antiviral Activity of Certain 2-(Alkylthio)- and 2-(Benzylthio)-5,6-dichloro-1-(.beta.-D-ribofuranosyl)benzimidazoles

Devivar

Kawashima²,

Revankar³

et al. 1994

J. Med. Chem.

View full text Add to dashboard Cite

Several 2-alkylthio- and 2-benzylthio derivatives of 5,6-dichloro-1-(beta-D-ribofuranosyl)benzimidazole (DRB) have been designed and synthesized from 5,6-dichloro-1-(beta-D-ribofuranosyl)-benzimidazole-2-thione. All compounds were evaluated for activity against human cytomegalovirus (HCMV) and/or herpes simplex virus type-1 (HSV-1). Three different cytotoxicity assays were used to determine if the compounds were toxic to uninfected cells. Most of the 2-alkylthio compounds were either inactive against HCMV and HSV-1 or were active only at concentrations at or near those which produced toxicity in uninfected cells. The best separation between activity against HCMV and cytotoxicity was observed with the 2-benzylthio analog 7. This prompted us to synthesize the substituted 2-benzylthio analogs 11-23 using a Topliss Tree approach. None of these compounds were more active than compound 7; most of the analogs were weakly active against both HCMV and HSV-1, but the activity was not separated from cytotoxicity. On the basis of both antiviral and cytotoxicity data, compound 7 was the best compound in the series. It was more active against HCMV than DRB (the 2-unsubstituted analog), acyclovir, and foscarnet, but it was less active than ganciclovir.

show abstract

Section: Introductionmentioning

confidence: 60%

Benzimidazole Ribonucleosides: Design, Synthesis, and Antiviral Activity of Certain 2-(Alkylthio)- and 2-(Benzylthio)-5,6-dichloro-1-(.beta.-D-ribofuranosyl)benzimidazoles

Devivar

Kawashima²,

Revankar³

et al. 1994

J. Med. Chem.

View full text Add to dashboard Cite

show abstract

“…Third, a kinase, which must be an early protein, leads within the early period to a complete phosphorylation of S2. At the stage in infection (60 min in our experimental system) the early viral mRNAs are preferentially translated [40]. The phosphorylation of S13 thus begins, and also depends on an early vaccinia synthesis [3] (and discussed above).…”

Section: Discussionmentioning

confidence: 99%

Ribosomal protein phosphorylation in vivo and in vitro by vaccinia virus

Buendia

Person-Fernandez

Beaud

et al. 1987

European Journal of Biochemistry

View full text Add to dashboard Cite

Ribosomal protein phosphorylation was investigated in Ehrlich ascites tumor cells infected with vaccinia virus (Copenhagen strain). After 90 rnin of simultaneous infection and 32P-labelling, ribosomal proteins Sa, S2 and S13 appear specifically phosphorylated as well as Sb/La, P1 and S6, which are also phosphorylated in control cells. Sa is an acidic protein, whose phosphorylation has not been observed previously. A kinetic study showed that S2 is phosphorylated very rapidly within 10 min after the beginning of infection and it is complete 1 h later. The phosphorylation of S13 begins after a lag time of about 1 h and is completed after about 2.5 h of infection. Moreover only one phosphate is incorporated into S13 on a serine residue while up to four phosphates are incorporated into S2, the first on a serine and the three following on threonine residues. In vivo experiments, carried out in the presence of cycloheximide and cordycepin, suggest a viral origin for the kinase involved in the phosphorylation of S2 and S13. Moreover, in vitro experiments demonstrated that the kinase associated with the viral cores is capable of phosphorylating S2 on a serine residue only. In our cell/virus system, no significant difference in S6 phosphorylation was detected, when compared to uninfected cells. It is concluded that the specific and efficient phosphorylation of three ribosomal proteins from the 40 S ribosomal subunit correlate well with possible translational mechanisms ensuring the efficient expression of early and late genes of vaccinia virus. In the light of these and previous results [Person, A. and Beaud, G. (1986) J. Biol. Chern. 261, 8283-82891, a mechanism is proposed for the shut-off of host protein synthesis and the selective translation of mRNAs of viral origin.Infection of cells with vaccinia virus, a DNA virus replicating in the cytoplasm [l], results in a shut-off of host protein synthesis concomittant to the translation of the viral early mRNAs transcribed from vaccinia cores. It was shown by Kaerlein and Horak that several ribosomal proteins of HeLa cells are modified after infection with vaccinia virus (WR strain) and they suggested a possible role of the phosphorylation of S2, S6 and S16 in the establishment of the shut-off of host protein synthesis [2, 31. These authors gave evidence that the protein kinase known to be associated with vaccinia virions [4-71 may play a role in the phosphorylation of the ribosomal proteins but an early virus-induced enzyme was also responsible for this effect [3].A protein-synthesis inhibitor, associated with vaccinia virions, has been recently purified yielding a 1 1-kDa basic protein [8]. This inhibitor is clearly different from vacciniaassociated protein kinase and is likely to be responsible for the shut-off of protein synthesis shown to occur in the absence of viral gene expression in several cell/vaccinia virus systems. Thus it has been supposed that, in a productive infection, a viral-coded protein is produced in sufficient amounts to re-

show abstract

“…In particular, ORB markedly inhibits the multiplication of vaccinia virus Tamm and Overman, 1957;Bucknall, 1967). However, ORB does not inhibit cytoplasmic vaccinia gene expression, but it impairs viral DNA encapsidation (Pothier et al, 1981). In addition to its in vitro antiviral effects (Sehgal and Tamm, 1980), ORB has been shown to suppress the replication of influenza virus in embryonic chicken eggs and in mice (Tamm et aI., 1954).…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Biological Evaluation of New 5,6-dichlorobenzimidazole Nucleoside Derivatives

Gosselin

Philouze

Bergogne

et al. 1994

Antivir Chem Chemother

View full text Add to dashboard Cite

Novel 5,6-dichlorobenzimidazole nucleoside analogues structurally related to the well-known riboside DRB have been synthesized. The 1′,2′- trans nucleosides were prepared by condensation of peracylated sugars with 5,6-dichlorobenzimidazole, whereas the 1′,2′- cis β-D-arabinofuranosyl and β-D-lyxofuranosyl nucleosides were obtained by inversion of configuration on the sugar moiety. Chiral acyclic derivatives were stereospecifically prepared by ring-opening of furano- or pyrano-nucleosides by means of periodate oxidation, followed by borohydride reduction. The in vitro activities against a range of DNA and RNA viruses, as well as the cytotoxicities in human T-lymphocyte MT-4 cells, have been determined for these novel compounds and for DRB. No truly selective activity (i.e. clearly below the cytotoxic concentration) was observed against any of the viruses used. Some of the compounds, including DRB, were cytotoxic to MT-4 cells at CC50 values of less than 10 μg ml−1.

show abstract

The Inhibition of Vaccinia Virus Replication by 5,6-Dichloro-1-beta-D-ribofuranosylbenzimidazole (DRB): an Effect at the Assembly Stage

Cited by 13 publications

References 18 publications

Benzimidazole Ribonucleosides: Design, Synthesis, and Antiviral Activity of Certain 2-(Alkylthio)- and 2-(Benzylthio)-5,6-dichloro-1-(.beta.-D-ribofuranosyl)benzimidazoles

Benzimidazole Ribonucleosides: Design, Synthesis, and Antiviral Activity of Certain 2-(Alkylthio)- and 2-(Benzylthio)-5,6-dichloro-1-(.beta.-D-ribofuranosyl)benzimidazoles

Ribosomal protein phosphorylation in vivo and in vitro by vaccinia virus

Synthesis and Biological Evaluation of New 5,6-dichlorobenzimidazole Nucleoside Derivatives

Contact Info

Product

Resources

About