5-Azacytosine Compounds In Medicinal Chemistry: Current Stage And Future Perspectives

Krečmerová, Marcela; Otmar, Miroslav

doi:10.4155/fmc.12.36

Cited by 16 publications

(14 citation statements)

References 80 publications

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“…2C). Taken together, these data suggest that the observed decreases in cellular viability are due to reduced proliferation rather than direct cytotoxicity, as is expected based upon the effects of these drugs on cellular physiology (56,57). Given the relatively small reductions in cellular viability at the doses used, the large decreases in viral titer observed with each of the three nucleosides ( Fig.…”

Section: Anti-influenza Virus Effects Of Nucleoside Analogsmentioning

confidence: 64%

“…The fact that favipiravir, which is currently in clinical trials as an influenza therapy, also functions as a lethal mutagen suggests the clinical relevance of this strategy. Current drawbacks to using nucleoside analogs clinically as antivirals are off-target effects and their relatively low potency (27,56,57). If novel mutagenic nucleoside analogs that overcome these hurdles can be identified, lethal mutagenesis may emerge as an effective strategy for treating a broad spectrum of RNA viruses, including influenza virus.…”

Section: Discussionmentioning

confidence: 99%

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Effective Lethal Mutagenesis of Influenza Virus by Three Nucleoside Analogs

Pauly

Lauring

2015

J Virol

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Lethal mutagenesis is a broad-spectrum antiviral strategy that exploits the high mutation rate and low mutational tolerance of many RNA viruses. This approach uses mutagenic drugs to increase viral mutation rates and burden viral populations with mutations that reduce the number of infectious progeny. We investigated the effectiveness of lethal mutagenesis as a strategy against influenza virus using three nucleoside analogs, ribavirin, 5-azacytidine, and 5-fluorouracil. All three drugs were active against a panel of seasonal H3N2 and laboratory-adapted H1N1 strains. We found that each drug increased the frequency of mutations in influenza virus populations and decreased the virus' specific infectivity, indicating a mutagenic mode of action. We were able to drive viral populations to extinction by passaging influenza virus in the presence of each drug, indicating that complete lethal mutagenesis of influenza virus populations can be achieved when a sufficient mutational burden is applied. Population-wide resistance to these mutagenic agents did not arise after serial passage of influenza virus populations in sublethal concentrations of drug. Sequencing of these drug-passaged viral populations revealed genome-wide accumulation of mutations at low frequency. The replicative capacity of drug-passaged populations was reduced at higher multiplicities of infection, suggesting the presence of defective interfering particles and a possible barrier to the evolution of resistance. Together, our data suggest that lethal mutagenesis may be a particularly effective therapeutic approach with a high genetic barrier to resistance for influenza virus. IMPORTANCEInfluenza virus is an RNA virus that causes significant morbidity and mortality during annual epidemics. Novel therapies for RNA viruses are needed due to the ease with which these viruses evolve resistance to existing therapeutics. Lethal mutagenesis is a broad-spectrum strategy that exploits the high mutation rate and the low mutational tolerance of most RNA viruses. It is thought to possess a higher barrier to resistance than conventional antiviral strategies. We investigated the effectiveness of lethal mutagenesis against influenza virus using three different drugs. We showed that influenza virus was sensitive to lethal mutagenesis by demonstrating that all three drugs induced mutations and led to an increase in the generation of defective viral particles. We also found that it may be difficult for resistance to these drugs to arise at a population-wide level. Our data suggest that lethal mutagenesis may be an attractive anti-influenza strategy that warrants further investigation. I nfluenza virus is a single-stranded, negative-sense RNA virus with a genome consisting of 8 segments (1). Like other RNA viruses, influenza virus replicates with extremely low fidelity. Its RNA-dependent RNA polymerase (RdRp) complex, which includes the viral proteins PB1, PB2, PA, and NP (2, 3), has a mutation rate of approximately 2.3 ϫ 10 Ϫ5 substitutions per nucleotide per cell ...

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Section: Anti-influenza Virus Effects Of Nucleoside Analogsmentioning

confidence: 64%

Section: Discussionmentioning

confidence: 99%

Effective Lethal Mutagenesis of Influenza Virus by Three Nucleoside Analogs

Pauly

Lauring

2015

J Virol

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“…Column chromatography was performed on silica gel 60 lm (Fluka). 1 H, 13 C and 31 P NMR spectra were measured on Bruker AVANCE III 500 and/ or 600 spectrometers equipped with a cryoprobe and operating at 500.0 or 600.1 MHz ( 1 H), and 125.7 or 150.9 MHz ( 13 C). 31 P NMR spectra were measured on Bruker AVANCE III 400 spectrometer operating at 202.3 MHz ( 31 P).…”

Section: Generalmentioning

confidence: 99%

“…The development of 5-azacytosine ANPs was initiated in our laboratory in order to search for new demethylating (epigenetic) drugs similar to 5-azacytosine nucleosides. 13 Although none of the new compounds fulfilled this criterion, we managed to find a new class of antiviral agents, 5-azacytosine analogue of cidofovir 1-(S)-[3-hydroxy-2-(phosphonomethoxy)propyl]-5azacytosine (HPMP-5-azaC) and various ester prodrugs derived from its cyclic form ( Fig. 2).…”

Section: Introductionmentioning

confidence: 99%

New prodrugs of two pyrimidine acyclic nucleoside phosphonates: Synthesis and antiviral activity

Krečmerová

Dračínský

Snoeck

et al. 2017

Bioorganic & Medicinal Chemistry

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New 2,4-diamino-6-[2-(phosphonomethoxy)ethoxy]pyrimidine (PMEO-DAPy) and 1-[2-(phosphonomethoxy)ethyl]-5-azacytosine (PME-5-azaC) prodrugs were prepared with a pro-moiety consisting of carbonyloxymethyl esters (POM, POC), alkoxyalkyl esters, amino acid phosphoramidates and/or tyrosine. The activity of the prodrugs was evaluated in vitro against different virus families. None of the synthesized prodrugs demonstrated activity against RNA viruses but some of them proved active against herpesviruses [including herpes simplex virus (HSV), varicella-zoster virus (VZV), and human cytomegalovirus (HCMV)]. The bis(POC) and the bis(amino acid) phosphoramidate prodrugs of PMEO-DAPy inhibited herpesvirus replication at lower doses than the parent compound although the selectivity against HSV and VZV was only slightly improved compared to PMEO-DAPy. The mono-octadecyl ester of PME-5-azaC emerged as the most potent and selective PME-5-azaC prodrug against HSV, VZV and HCMV with EC's of 0.15-1.12µM while PME-5-azaC only had marginal anti-herpesvirus activity. Although the bis(hexadecylamido-l-tyrosyl) and the bis(POM) esters of PME-5-azaC were also very potent anti-herpesvirus drugs, these were less selective than the mono-octadecyl ester prodrug.

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“…For example, DNA methylated at promoter CpG islands is associated with gene silencing and can be reversed by treatment with DNA methyltransferase inhibitors such as 5-AZA (5-aza-2′-deoxycytidine) leading to the reactivation of silenced genes (Baylin and Jones, 2011; Krecmerova and Otmar, 2012). Similarly, chromatin structure can alter accessibility to the DNA template and can be readily remodeled by histone post-translational modifications (PTMs).…”

Section: Introductionmentioning

confidence: 99%

Exploiting tumor epigenetics to improve oncolytic virotherapy

Forbes¹,

Abdelbary²,

Lupien³

et al. 2013

Front. Genet.

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Oncolytic viruses (OVs) comprise a versatile and multi-mechanistic therapeutic platform in the growing arsenal of anticancer biologics. These replicating therapeutics find favorable conditions in the tumor niche, characterized among others by increased metabolism, reduced anti-tumor/antiviral immunity, and disorganized vasculature. Through a self-amplification that is dependent on multiple cancer-specific defects, these agents exhibit remarkable tumor selectivity. With several OVs completing or entering Phase III clinical evaluation, their therapeutic potential as well as the challenges ahead are increasingly clear. One key hurdle is tumor heterogeneity, which results in variations in the ability of tumors to support productive infection by OVs and to induce adaptive anti-tumor immunity. To this end, mounting evidence suggests tumor epigenetics may play a key role. This review will focus on the epigenetic landscape of tumors and how it relates to OV infection. Therapeutic strategies aiming to exploit the epigenetic identity of tumors in order to improve OV therapy are also discussed.

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5-Azacytosine Compounds In Medicinal Chemistry: Current Stage And Future Perspectives

Cited by 16 publications

References 80 publications

Effective Lethal Mutagenesis of Influenza Virus by Three Nucleoside Analogs

Effective Lethal Mutagenesis of Influenza Virus by Three Nucleoside Analogs

New prodrugs of two pyrimidine acyclic nucleoside phosphonates: Synthesis and antiviral activity

Exploiting tumor epigenetics to improve oncolytic virotherapy

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