Acyclic Phosphonomethylether Nucleoside Inhibitors of Respiratory Viruses

Barnard, Dale L.; Bischofberger, Norbert; Kim, C. U.; Huffman, John H.; Sidwell, Robert W.; Dougherty, Joseph P.; Lew, Willard; Williams, Matthew A.; Yang, Wengang

doi:10.1177/095632029700800306

Cited by 15 publications

(16 citation statements)

References 23 publications

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“…To determine the effect of the guanosine analogue ribavirin on production of infectious EBOV in vitro, eGFP-ZEBOV was grown at a low MOI in Vero E6 cells with media containing a range of concentrations of ribavirin. Consistent with other published reports, ribavirin-induced cytotoxicity was not observed at the concentrations used (18,35,36). Viral titers of the supernatants revealed that increasing concentrations of ribavirin resulted in decreasing quantities of infectious virus (Fig.…”

Section: Effect Of Guanosine Analogue On Ebola Virus Mutation Frequensupporting

confidence: 80%

Determination and Therapeutic Exploitation of Ebola Virus Spontaneous Mutation Frequency

Alfson

Worwa

Carrión

et al. 2016

J Virol

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Ebola virus (EBOV) is an RNA virus that can cause hemorrhagic fever with high fatality rates, and there are no approved vaccines or therapies. Typically, RNA viruses have high spontaneous mutation rates, which permit rapid adaptation to selection pressures and have other important biological consequences. However, it is unknown if filoviruses exhibit high mutation frequencies. Ultradeep sequencing and a recombinant EBOV that carries the gene encoding green fluorescent protein were used to determine the spontaneous mutation frequency of EBOV. The effects of the guanosine analogue ribavirin during EBOV infections were also assessed. Ultradeep sequencing revealed that the mutation frequency for EBOV was high and similar to those of other RNA viruses. Interestingly, significant genetic diversity was not observed in viable viruses, implying that changes were not well tolerated. We hypothesized that this could be exploited therapeutically. In vitro, the presence of ribavirin increased the error rate, and the 50% inhibitory concentration (IC 50 ) was 27 M. In a mouse model of ribavirin therapy given pre-EBOV exposure, ribavirin treatment corresponded with a significant delay in time to death and up to 75% survival. In mouse and monkey models of therapy given post-EBOV exposure, ribavirin treatment also delayed the time to death and increased survival. These results demonstrate that EBOV has a spontaneous mutation frequency similar to those of other RNA viruses. These data also suggest a potential for therapeutic use of ribavirin for human EBOV infections. IMPORTANCEEbola virus (EBOV) causes a severe hemorrhagic disease with high case fatality rates; there are no approved vaccines or therapies. We determined the spontaneous mutation frequency of EBOV, which is relevant to understanding the potential for the virus to adapt. The frequency was similar to those of other RNA viruses. Significant genetic diversity was not observed in viable viruses, implying that changes were not well tolerated. We hypothesized that this could be exploited therapeutically. Ribavirin is a viral mutagen approved for treatment of several virus infections; it is also cheap and readily available. In cell culture, we showed that ribavirin was effective at reducing production of infectious EBOV. In mouse and monkey models of therapy given post-EBOV exposure, ribavirin treatment delayed the time to death and increased survival. These data provide a better understanding of EBOV spontaneous mutation and suggest that ribavirin may have great value in the context of human disease.

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Section: Effect Of Guanosine Analogue On Ebola Virus Mutation Frequensupporting

confidence: 80%

Determination and Therapeutic Exploitation of Ebola Virus Spontaneous Mutation Frequency

Alfson

Worwa

Carrión

et al. 2016

J Virol

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“…A neutral red assay of the same plate was done to verify the results from the CPE assay spectrophotometrically (see below). The usual correlation between the two assays has been greater than 95% (Barnard, 1997a).…”

Section: Cytopathic Effect Inhibition Assaymentioning

confidence: 99%

“…was added to each well in a small volume. At '0' time, the virus were added within 5 min of drug addition as described previously for the CPE inhibition assay (Barnard et al, 1997a from visual and NR assays as described above.…”

Section: Cytopathic Effect Inhibition Timing Assaymentioning

confidence: 99%

“…The protocol of Barnard et al (1997a) was used. Test compounds were tested at varying concentrations (seven 1/2 log 10 dilutions).…”

Section: Cytopathic Effect Inhibition Assaymentioning

confidence: 99%

“…This assay was done as described by Barnard et al (1997a). Virus (strain Chicago-1) was used to study the inhibition by selected compounds at different m.o.i.…”

Section: Multiplicity Of Infection Assaymentioning

confidence: 99%

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Inhibition of Measles Virus Replication by 5′-Nor Carbocyclic Adenosine Analogues

Barnard

Stowell

Seley

et al. 2001

Antivir Chem Chemother

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Despite intense efforts to increase vaccine coverage, measles virus (MV) still causes significant morbidity and mortality in the world, sometimes as the result of severe, chronic, lethal disease. In an effort to develop therapies to supplement immunization strategies, a number of 5′-nor carbocyclic adenosine analogues were evaluated for anti-MV activity in CV-1 monkey kidney cells. Of those compounds tested, those either unsubstituted at C4 or possessing a hydroxyl, azido or amino substituent at that position were the most active, with particularly significant inhibition of MV, strain Chicago-1. The EC50 values against this strain ranged from <0.1 to 1 mg/ml, as determined by cytopathic effect reduction assay, and confirmed by neutral red uptake. By virus yield reduction assay (+)-(1 S,2S,3R,4S)-4-(6′-amino-9'H-purin-9′- yl)cyclopentane-1,2,3-triol (2) (-)-(1R,2S,3R)-1-(6′- amino-9'H-purin-9′-yl)-2,3-dihydoxycyclopent-4- ene (3) (-)-(1R,2S,3R)-1-(6-amino-9H-purin-9- yl)cyclopentane-2,3-dihydoxycyclopentane (5) and (-)-(1R,2R,3R,4S)-4-amino-1-(6-amino-9H-purin-9- yl)cyclopentane-2,3-diol (8) were the most potent compounds tested, all with EC90 values of <0.4 mg/ml. Compounds 3 and 5 were also tested against other MV strains, and similarly inhibited those strains except for four designated as Bil, Edmonston, SA and X-1108. Compound 8 did not potently inhibit these other MV strains. In addition, 3, 5 and 8 demonstrated synergistic (additive) inhibition of MV replication in combination with ribavirin at several concentrations. Compounds 3, 5 and 8 were also potent MV inhibitors even when added to infected cells 24 h after virus exposure. None of these three compounds was virucidal at concentrations that inhibited viral replication as determined by virus yield reduction assay. Most compounds tested were also not toxic at concentrations >100 mg/ml in actively growing and stationary-phase cells. Results suggest that these compounds may be clinically useful anti-MV virus agents.

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Synthesis and Biological Activity of Isopolar Acyclic Nucleotide Analogs

Holý¹

2002

Recent Advances in Nucleosides: Chemistry and Chemotherapy

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Acyclic Phosphonomethylether Nucleoside Inhibitors of Respiratory Viruses

Cited by 15 publications

References 23 publications

Determination and Therapeutic Exploitation of Ebola Virus Spontaneous Mutation Frequency

Determination and Therapeutic Exploitation of Ebola Virus Spontaneous Mutation Frequency

Inhibition of Measles Virus Replication by 5′-Nor Carbocyclic Adenosine Analogues

Synthesis and Biological Activity of Isopolar Acyclic Nucleotide Analogs

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