Antiviral Activity of 3-Deazaguanine, 3-Deazaguanosine, and 3-Deazaguanylic Acid

Allen, Lois B.; Huffman, John H.; Cook, P. Dan; Meyer, Rich B.; Robins, Roland K.; Sidwell, Robert W.

doi:10.1128/aac.12.1.114

Cited by 44 publications

(6 citation statements)

References 9 publications

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“…These compounds are not particularly toxic in confluent monolayers (see Table 1), but inhibit cell proliferation (Allen et al, 1977; Balzarini et al, 1998; Crance et al, 2003; Stet et al, 1994). In these assays the cultures received treatment when started as sub-confluent monolayers.…”

Section: Resultsmentioning

confidence: 99%

“…Antiviral compounds selected for the study include 6-azauridine (Flint et al, 2014; Rada and Dragun, 1977; Smee et al, 1987), BCX4430 (Julander et al, 2014; Taylor et al, 2016), 3-deazaguanine (Allen et al, 1977; Smee et al, 2016), EICAR (De Clercq, 2015; De Clercq et al, 1991), favipiravir (Furuta et al, 2013; Mendenhall et al, 2011), Infergen™ (interferon alfacon 1, hereafter referred to as infergen) (Julander et al, 2007; Morrey et al, 2004), mycophenolic acid (Cline et al, 1969; Takhampunya et al, 2006; To et al, 2016), ribavirin (Sidwell et al, 1972; Smee et al, 1987; Westover et al, 2016), and tiazofurin (Baker et al, 2003; Huggins et al, 1984). All of the compounds have antiviral properties, but against different viruses.…”

Section: Introductionmentioning

confidence: 99%

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Evaluation of cell viability dyes in antiviral assays with RNA viruses that exhibit different cytopathogenic properties

Smee

Hurst

Evans

et al. 2017

Journal of Virological Methods

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Studies were conducted to determine the performance of four dyes in assessing antiviral activities of compounds against three RNA viruses with differing cytopathogenic properties. Dyes included alamarBlue® measured by absorbance (ALB-A) and fluorescence (ALB-F), neutral red (NR), Viral ToxGlo™ (VTG), and WST-1. Viruses were chikungunya, dengue type 2, and Junin, which generally cause 100, 80-90, and 50% maximal cytopathic effect (CPE), respectively, in Vero 76. Compounds evaluated were 6-azauridine, BCX-4430, 3-deazaguanine, EICAR, favipiravir, infergen, mycophenolic acid (MPA), ribavirin, and tiazofurin. The 50% virus-inhibitory (EC50) values for each inhibitor and virus combination did not vary significantly based on the dye used. However, dyes varied in distinguishing the vitality of virus-infected cultures when not all cells were killed by virus infection. For example, VTG uptake into dengue-infected cells was nearly 50% when visual examination showed only 10-20% cell survival. ALB-A measured infected cell viability differently than ALB-F as follows: 16% versus 32% (dengue-infected), respectively, and 51% versus 72% (Junin-infected), respectively. Cytotoxicity (CC50) assays with dyes in uninfected proliferating cells produced similar CC50 values for EICAR (1.5-8.9 μM) and MPA (0.8-2.5 μM). 6-Azauridine toxicity was 6.1-17.5 μM with NR, VTG, and WST-1, compared to 48-92 μM with ALB-A and ALB-F.(P<0.001). Curiously, the CC50 values for 3-deazaguanine were 83-93 μM with ALB-F versus 2.4-7.0 μM with all other dyes including ALB-A (P<0.001). Overall, ALB minimized the toxicities detected with these two inhibitors. Because the choice of dyes affected CC50 values, this impacted on the resulting in vitro selectivity indexes (calculated as CC50/EC50 ratio).

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Evaluation of cell viability dyes in antiviral assays with RNA viruses that exhibit different cytopathogenic properties

Smee

Hurst

Evans

et al. 2017

Journal of Virological Methods

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“…The modes of action of ribavirin and 3-deazaguanine have not been specifically identified against picornaviruses. Both compounds (once metabolized to 5’-monophosphate nucleotides) inhibit cellular inosine monophosphate dehydrogenase, resulting in decreases in intracellular guanosine triphosphate levels (Allen et al, 1977; Streeter et al, 1973). This affects the rates of viral and cellular RNA synthesis.…”

mentioning

confidence: 99%

Susceptibilities of enterovirus D68, enterovirus 71, and rhinovirus 87 strains to various antiviral compounds

et al. 2016

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Compounds were evaluated for antiviral activity in rhabdomyosarcoma (RD) cells against a recent 2014 clinical isolate of enterovirus D68 (EV-D68), a 1962 strain of EV-68D, rhinovirus 87 (RV-87, serologically the same as EV-D68), and enterovirus 71 (EV-71). Test substances included known-active antipicornavirus agents (enviroxime, guanidine HCl, pirodavir, pleconaril, and rupintrivir), nucleobase/nucleoside analogs (3-deazaguanine and ribavirin), and three novel epidithiodiketopiperazines (KCN-2,2’-epi-19, KCN-19, and KCN-21). Of these, rupintrivir was the most potent, with 50% inhibition of viral cytopathic effect (EC50) and 90% inhibition (EC90) of virus yield at 0.0022-0.0053 μM against EV-D68. Enviroxime, pleconaril and the KCN compounds showed efficacy at 0.01-0.3 μM; 3-deazaguanine and pirodavir inhibited EV-D68 at 7-13 μM, and guanidine HCl and ribavirin were inhibitory at 80-135 μM. Pirodavir was active against EV-71 (EC50 of 0.78 μM) but not against RV-87 or EV-D68, and all other compounds were less effective against EV-71 than against RV-87 and EV-D68. The most promising compound inhibiting both virus infections at low concentrations was rupintrivir. Antiviral activity was confirmed for the ten compounds in virus yield reduction (VYR) assays in RD cells, and for enviroxime, guanidine HCl, and pirodavir by cytopathic effect (CPE) assays in A549, HeLa-Ohio-1, and RD cells. These studies may serve as a basis for further pre-clinical discovery of anti-enterovirus inhibitors. Furthermore, the antiviral profiles and growth characteristics observed herein support the assertion that EV-D68 should be classified together with RV-87.

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“…3-Deazaguanosine has been reported to possess broad spectrum antiviral activity against a variety of DNA and RNA viruses, as well as antitumor activity against the L1210 leukemia and several mammary adenocarcinomas in mice. [16,17] 2-Vinylinosine is a modified nucleoside with broad-spectrum RNA antiviral activity against a number of virus including JEV, PIC, PT, VEE and YF. [18]…”

Section: Introductionmentioning

confidence: 99%

Base-Functionalized Carbocyclic Nucleosides: Design, Synthesis, and Mechanism of Antiviral Activity

Nair

Zhang

et al. 2009

Nucleosides, Nucleotides & Nucleic Acids

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New carbocyclic ribonucleosides with unsaturated groups at the C-2 position of the nucleobase were designed as potential RNA antiviral compounds. The design was based on the expectation that the monophosphates of these compounds would be inhibitors of the enzyme, IMPDH. Appropriate methodologies were developed to achieve the target molecules. Results from the initial in vitro antiviral studies are mentioned. The IMPDH-associated mechanism of the antiviral activity of the most active compound is supported by enzyme inhibition studies.

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Antiviral Activity of 3-Deazaguanine, 3-Deazaguanosine, and 3-Deazaguanylic Acid

Cited by 44 publications

References 9 publications

Evaluation of cell viability dyes in antiviral assays with RNA viruses that exhibit different cytopathogenic properties

Evaluation of cell viability dyes in antiviral assays with RNA viruses that exhibit different cytopathogenic properties

Susceptibilities of enterovirus D68, enterovirus 71, and rhinovirus 87 strains to various antiviral compounds

Base-Functionalized Carbocyclic Nucleosides: Design, Synthesis, and Mechanism of Antiviral Activity

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