The importance of IMP dehydrogenase inhibition in the broad spectrum antiviral activity of ribavirin and selenazofurin

Robins, Roland K.; Revankar, Ganapathi R.; McKernan, Patricia A.; Murray, Byron K.; Kirsi, Jorma J.; North, James A.

doi:10.1016/0065-2571(85)90068-8

Cited by 51 publications

(29 citation statements)

References 36 publications

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“…Because ribavirin activity against cowpox virus was not fully reversible by extracellular guanosine treatment, this may support the role of other modes of action of ribavirin against poxviruses besides IMPDH inhibition. In a related study, Robins et al (1986) reported achieving only a partial reversal of ribavirin inhibition of vaccinia virus replication in Vero 76 cells by extracellular guanosine treatment. The extensive comparisons presented here that correlate intracellular GTP pool levels with degrees of virus inhibition under a variety of conditions, support the role of IMPDH inhibition in antipoxvirus activity, but do not exclude other inhibitory modes of action in the case of ribavirin.…”

Section: Discussionmentioning

confidence: 99%

Antiviral Activity and Mode of Action Studies of Ribavirin and Mycophenolic Acid against Orthopoxviruses in Vitro

Smee

Bray

Huggins

2001

Antivir Chem Chemother

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triphosphate forms of the drug compared with Vero 76 cells. For both MPA and ribavirin, virus inhibition was closely correlated to the extent of suppression of intracellular guanosine triphosphate (GTP) pools. Treatment with extracellular guanosine (which restored intracellular GTP levels) did not lead to complete reversal of the anticowpox virus activity of ribavirin. This suggests that other modes of virus inhibition also appear to contribute to the anti-orthopoxvirus activity of ribavirin. Biological differences in mode of action and immunosuppressive potential between ribavirin and MPA may account for why the former compound is active against orthopoxvirus infections in animals and the latter inhibitor is not.

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Section: Discussionmentioning

confidence: 99%

Antiviral Activity and Mode of Action Studies of Ribavirin and Mycophenolic Acid against Orthopoxviruses in Vitro

Smee

Bray

Huggins

2001

Antivir Chem Chemother

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“…Ribavirin has been shown to diminish viral protein translation and RNA replication via three activities: as a mutagen by incorporation into nascent viral RNA molecules (8)(9)(10)12), by the inhibition of IMP dehydrogenase (IMPDH), which results in a decrease in intracellular GTP levels (25)(26)(27), and by immunomodulatory effects, including a switch in the T-helper cell phenotype from type 2 to type 1 (28)(29)(30)(31)(32). It has been suggested that during virus replication in newly synthesized genomes, a decrease in cellular GTP levels may increase the frequency of ribavirin incorporation in newly synthesized genomes during virus replication through competitive inhibition (9, 10, 12, 13).…”

Section: Discussionmentioning

confidence: 99%

Ribavirin-Resistant Mutants of Human Enterovirus 71 Express a High Replication Fidelity Phenotype during Growth in Cell Culture

Sadeghipour

Bek

McMinn

2013

J Virol

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It has been shown in animal models that ribavirin-resistant poliovirus with a G64S mutation in its 3D polymerase has high replication fidelity coupled with attenuated virulence. Here, we describe the effects of mutagenesis in the human enterovirus 71 (HEV71) 3D polymerase on ribavirin resistance and replication fidelity. Seven substitutions were introduced at amino acid position 3D-G64 of a HEV71 full-length infectious cDNA clone (26M). Viable clone-derived virus populations were rescued from the G64N, G64R, and G64T mutant cDNA clones. The clone-derived G64R and G64T mutant virus populations were resistant to growth inhibition in the presence of 1,600 M ribavirin, whereas the growth of parental 26M and the G64N mutant viruses were inhibited in the presence of 800 M ribavirin. Nucleotide sequencing of the 2C and 3D coding regions revealed that the rate of random mutagenesis after 13 passages in the presence of 400 M ribavirin was nearly 10 times higher in the 26M genome than in the mutant G64R virus genome. Furthermore, random mutations acquired in the 2C coding regions of 26M and G64N conferred resistance to growth inhibition in the presence of 0.5 mM guanidine, whereas the G64R and G64T mutant virus populations remained susceptible to growth inhibition by 0.5 mM guanidine. Interestingly, a S264L mutation identified in the 3D coding region of 26M after ribavirin selection was also associated with both ribavirin-resistant and high replication fidelity phenotypes. These findings are consistent with the hypothesis that the 3D-G64R, 3D-G64T, and 3D-S264L mutations confer resistance upon HEV71 to the antiviral mutagen ribavirin, coupled with a high replication fidelity phenotype during growth in cell culture.

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“…Symbols: F, placebo-treated cowpox-WT virus-infected mice; s, cidofovir-treated cowpox-WT virus-infected mice; E, placebo-treated cowpox-R (SF) virus-infected mice; ᮀ, cidofovir-treated cowpox-R (SF) virus-infected mice. (23,27) whereas cidofovir is a viral DNA polymerase inhibitor (34). Application of these data to a possible clinical situation suggests the possibility that treatment of variola or monkeypox virus infections in humans could lead to the emergence of CDV-R viruses that are cross resistant to other antiviral compounds.…”

Section: Fig 2 Treatment Of Intranasal Infections Withmentioning

confidence: 99%

“…The sensitivities of the plaquepurified WT and CDV-R poxviruses to selected antiviral compounds were determined in six-well plates of Vero 76 cells. The selected compounds represented different classes of antiviral agents, such as those inhibiting viral DNA polymerases (cidofovir, cyclic HPMPC, and HPMPA) (34), IMP dehydrogenase inhibitors (ribavirin and MPA) (11,23), and C-c 3 Ado, an inhibitor of S-adenosylhomocysteine hydrolase (10). Plates of cells were infected with about 100 PFU of virus per well, the virus was adsorbed for 1.5 to 2 h, and then twofold dilutions of antiviral compounds were applied.…”

mentioning

confidence: 99%

Characterization of Wild-Type and Cidofovir-Resistant Strains of Camelpox, Cowpox, Monkeypox, and Vaccinia Viruses

Smee

Sidwell

Kefauver

et al. 2002

Antimicrob Agents Chemother

125

100

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The importance of IMP dehydrogenase inhibition in the broad spectrum antiviral activity of ribavirin and selenazofurin

Cited by 51 publications

References 36 publications

Antiviral Activity and Mode of Action Studies of Ribavirin and Mycophenolic Acid against Orthopoxviruses in Vitro

Antiviral Activity and Mode of Action Studies of Ribavirin and Mycophenolic Acid against Orthopoxviruses in Vitro

Ribavirin-Resistant Mutants of Human Enterovirus 71 Express a High Replication Fidelity Phenotype during Growth in Cell Culture

Characterization of Wild-Type and Cidofovir-Resistant Strains of Camelpox, Cowpox, Monkeypox, and Vaccinia Viruses

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