Relationship between structure of benzimidazole derivatives and inhibitory activity on vaccinia virus multiplication

Tamm, Igor; Overman, John R.

doi:10.1016/0042-6822(57)90032-6

Cited by 31 publications

(17 citation statements)

References 13 publications

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“…MRL-1237 was consistently more effective against enteroviruses than both guanidine hydrochloride and HBB. Among polioviruses, a type 2 strain was most sensitive, and type 1 strains were least sensitive to HBB, as previously described (26,66). Such an antiviral profile of HBB was similar to that of MRL-1237.…”

Section: Antiviral Activity Of Mrl-1237supporting

confidence: 52%

“…1), were shown to have selective antipicornavirus activity (25,26). To develop safer and more potent chemotherapeutic agents against picornaviruses, attempts to evaluate newly synthesized benzimidazole derivatives have been undertaken (1,23,25,26,37,(66)(67)(68)76). Previous reports showed that HBB inhibited viral RNA synthesis in a manner similar to guanidine, but there was little cross-resistance between these two agents (7,67).…”

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confidence: 99%

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Mutations in the 2C Region of Poliovirus Responsible for Altered Sensitivity to Benzimidazole Derivatives

Shimizu

Agoh

et al. 2000

J Virol

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MRL-1237, [1-(4-fluorophenyl)-2-(4-imino-1,4-dihydropyridin-1-yl) methylbenzimidazole hydrochloride], is a potent and selective inhibitor of the replication of enteroviruses. To reveal the target molecule of MRL-1237 in viral replication, we selected spontaneous MRL-1237-resistant poliovirus mutants. Of 15 MRL-1237-resistant mutants obtained, 14 were cross-resistant to guanidine hydrochloride (mrgr), while 1 was susceptible (mrgs). Sequence analysis of the 2C region revealed that the 14 mrgr mutants contained a single nucleotide substitution that altered an amino acid residue from Phe-164 to Tyr. The mrgs mutant, on the other hand, contained a substitution of Ile-120 to Val. Through the construction of a cDNA-derived mutant, we confirmed that the single mutation at Phe-164 was really responsible for the reduced susceptibility to MRL-1237. MRL-1237 inhibited poliovirus-specific RNA synthesis in HeLa cells infected with a wild strain but not with an F164Y mutant. We furthermore examined the effect of mutations of the 2C region on the drug sensitivity of cDNA-derived guanidine-resistant and -dependent mutants. Two guanidine-resistant mutants were crossresistant to MRL-1237 but remained susceptible to another benzimidazole, enviroxime. Either MRL-1237 or guanidine stimulated the viral replication of two guanidine-dependent mutants, but enviroxime did not. These results indicate that MRL-1237, like guanidine, targets the 2C protein of poliovirus for its antiviral effect.Poliovirus is a member of the family Picornaviridae, containing a positive-sense, single-stranded RNA as a viral genome. The genome encodes a single precursor polyprotein which is eventually cleaved to four structural and seven nonstructural proteins (58). The structural capsid proteins of picornaviruses are located at the amino-terminal P1 region of the polyprotein. The remainder contains viral nonstructural proteins, including two proteases (2A pro and 3C pro ), an RNA-dependent RNA polymerase (3D pol ), and several other proteins essential for viral RNA synthesis. In poliovirus-infected cells, nonstructural proteins 2B, 2C, 3A, 3B, and 3D and their precursors are associated with a specific structure of virus-induced cytoplasmic membranous vesicles, the so-called replication complex (13,22), and implicated in viral RNA synthesis together with viral RNA and some cellular proteins (13,14,17,22,44,61,64,65,73).The 2C protein of picornaviruses contains conserved nucleoside triphosphate (NTP)-binding and RNA helicase motifs in its middle region (19,(28)(29)(30)(31). Genetically manipulated mutations in the NTP-binding motif of the poliovirus 2C protein abolished viral replication and RNA synthesis (47, 70). The replication of viruses with such mutations in the NTP-binding motif was poorly complementated in trans (71). These results indicate the functional significance of the NTP-binding motif in viral replication. A recombinant poliovirus 2C (or precursor 2BC) protein fused with maltose-binding protein (MBP), MBP-2C, was expressed in Escherichia coli and...

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Section: Antiviral Activity Of Mrl-1237supporting

confidence: 52%

mentioning

confidence: 99%

Mutations in the 2C Region of Poliovirus Responsible for Altered Sensitivity to Benzimidazole Derivatives

Shimizu

Agoh

et al. 2000

J Virol

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“…With regard to ORB, there are apparent anomalies between the previous reports of its activity against vaccinia virus Tamm and Overman, 1957) and our data. Although we have no definite explanation for this discrepancy, a contributing factor may be the different cell types used, namely E 6SM in our studies vs. the chorioallantoic membrane of chicken eggs in the work by Overman and Tamm (1957).…”

Section: Discussioncontrasting

confidence: 55%

“…A more interesting feature of ORB is its ability to block tat-dependent human immunodeficiency virus (HIV) RNA modification (Braddock et et., 1991), and to inhibit the multiplication of several RNA and DNA viruses in cell culture systems (reviewed by Sehgal and Tamm, 1980). 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).…”

Section: Introductionmentioning

confidence: 99%

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

Gosselin

Philouze

Bergogne

et al. 1994

Antivir Chem Chemother

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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.

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“…The dichloro-and trichloro-ribofuranosyl benzimidazoles (DRB and TRB) have been reported to be active against influenza A and B and vaccinia viruses in chick chorioallantoic membrane (Tamm et aL 1954;Tamm, 1956a;Tamm & Overman, 1957), and against polio virus and adenovirus 4 in monkey kidney cells (Tamm & Nemes, 1957;Tamm, Nemes & Osterhout, 1960). Following the discovery by Allfrey, Mirsky & Osawa (1957) that DRB strongly inhibited RNA synthesis in isolated calf thymus nuclei, Tamm, Nemes & Osterhout (1960) proposed that the wide spectrum of antiviral activity of DRB was due to its effects on RNA synthesis, and the mode of action of TRB is probably similar.…”

Section: Introductionmentioning

confidence: 99%

The Effects of Substituted Benzimidazoles on the Growth of Viruses and the Nucleic Acid Metabolism of Host Cells

Bucknall¹

1967

Journal of General Virology

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Relationship between structure of benzimidazole derivatives and inhibitory activity on vaccinia virus multiplication

Cited by 31 publications

References 13 publications

Mutations in the 2C Region of Poliovirus Responsible for Altered Sensitivity to Benzimidazole Derivatives

Mutations in the 2C Region of Poliovirus Responsible for Altered Sensitivity to Benzimidazole Derivatives

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

The Effects of Substituted Benzimidazoles on the Growth of Viruses and the Nucleic Acid Metabolism of Host Cells

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