Characterization of β-
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            -Hydroxycytidine as a Novel Inhibitor of Chikungunya Virus

Ehteshami, Maryam; Tao, Sijia; Zandi, Keivan; Hsiao, Hui-Mien; Jiang, Yong; Hammond, Emily T.; Amblard, Franck; Russell, Olivia; Merits, Andres; Schinazi, Raymond F.

doi:10.1128/aac.02395-16

Cited by 76 publications

(61 citation statements)

References 24 publications

(25 reference statements)

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“…These data demonstrate the activity of NHC against a panel of respiratory viruses associated with influenza-like diseases. Combined with the previously reported antiviral activity of NHC in cell culture against some Flaviviridae, Coronaviridae, and Togaviridae family members (36)(37)(38)(39), these data establish the broadspectrum activity of the compound against different positive-and negative-strand RNA virus families and, in the case of IAV infection, spotlight the potential for synergistic combination with the current SOC.…”

Section: Resultssupporting

confidence: 67%

Orally Efficacious Broad-Spectrum Ribonucleoside Analog Inhibitor of Influenza and Respiratory Syncytial Viruses

Yoon

Toots

Lee

et al. 2018

Antimicrob Agents Chemother

181

207

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Morbidity and mortality resulting from influenza-like disease are a threat, especially for older adults. To improve case management, next-generation broad-spectrum antiviral therapeutics that are efficacious against major drivers of influenza-like disease, including influenza viruses and respiratory syncytial virus (RSV), are urgently needed. Using a dual-pathogen high-throughput screening protocol for influenza A virus (IAV) and RSV inhibitors, we have identified -hydroxycytidine (NHC) as a potent inhibitor of RSV, influenza B viruses, and IAVs of human, avian, and swine origins. Biochemical polymerase assays and viral RNA sequencing revealed that the ribonucleotide analog is incorporated into nascent viral RNAs in place of cytidine, increasing the frequency of viral mutagenesis. Viral passaging in cell culture in the presence of an inhibitor did not induce robust resistance. Pharmacokinetic profiling demonstrated dose-dependent oral bioavailability of 36 to 56%, sustained levels of the active 5'-triphosphate anabolite in primary human airway cells and mouse lung tissue, and good tolerability after extended dosing at 800 mg/kg of body weight/day. The compound was orally efficacious against RSV and both seasonal and highly pathogenic avian IAVs in mouse models, reducing lung virus loads and alleviating disease biomarkers. Oral dosing reduced IAV burdens in a guinea pig transmission model and suppressed virus spread to uninfected contact animals through direct transmission. Based on its broad-spectrum efficacy and pharmacokinetic properties, NHC is a promising candidate for future clinical development as a treatment option for influenza-like diseases.

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Section: Resultssupporting

confidence: 67%

Orally Efficacious Broad-Spectrum Ribonucleoside Analog Inhibitor of Influenza and Respiratory Syncytial Viruses

Yoon

Toots

Lee

et al. 2018

Antimicrob Agents Chemother

181

207

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“…Nevertheless, this compound did not inhibit TBEV reproduction at 50 μM concentration. In the previous studies NHC was shown to inhibit the replication of viruses with various genomes and replication cycles: (+)ssRNA genomic bovine viral diarrhea (BVDV) and hepatitis C (HCV) viruses, both belonging to Flaviviridae family, severe acute respiratory syndrome‐associated coronavirus, norovirus, chikungunya virus; (‐)ssRNA genomic Ebola virus, and DNA genomic vaccinia, monkeypox, and cowpox viruses (family Poxviridae ) . However, it is not active against HIV‐1, hepatitis B virus, and herpes simplex viruses .…”

Section: Resultsmentioning

confidence: 99%

Selective Inhibition of Enterovirus A Species Members’ Reproduction by Furano[2, 3‐d]pyrimidine Nucleosides Revealed by Antiviral Activity Profiling against (+)ssRNA Viruses

et al. 2018

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The rational design of broad‐spectrum antivirals requires data on antiviral activity of compounds against multiple viruses, which are often not available. We have developed a panel of (+)ssRNA viruses composed of Enterovirus and Flavivirus genera members allowing to study these activity spectra. Antiviral activity profiling of a set of nucleoside analogues revealed N4‐hydroxycytidine as an efficient inhibitor of replication of coxsackieviruses and other enteroviruses, but ineffective against tick‐borne encephalitis virus. Furano[2, 3‐d]pyrimidine nucleosides with n‐pentyl or n‐hexyl tails showed selective inhibition of Enterovirus A representatives. 5‐(Tetradec‐1‐yn‐1‐yl)‐uridine showed selective inhibition of tick‐borne encephalitis virus at the micromolar level.

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“…2). Previous studies showed that in cultured cells, NHC is rapidly converted into mono-, di-, and triphosphate forms, along with other metabolites, such as CTP and UTP (22,25,37). Because the levels of the NHC-triphosphate form (NHC-TP) were highest among the intracellular metabolites, it was proposed as the metabolite primarily responsible for the antiviral effect of NHC (22).…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies demonstrated that NHC significantly inhibits replication of hepatitis C virus (HCV) replicon and bovine viral diarrhea virus in Huh7 and MDBK cells, respectively (22). NHC was also capable of inhibiting human norovirus replicon in HG23 cells (23), human coronavirus (24), and chikungunya virus (25). It was reasonable to expect that the antiviral effect of this nucleoside analog is not limited to these few viruses, and might also be effective against other viral species with RNA genomes, such as VEEV.…”

mentioning

confidence: 99%

β- d - N ⁴ -Hydroxycytidine Is a Potent Anti-alphavirus Compound That Induces a High Level of Mutations in the Viral Genome

Urakova

Kuznetsova

Crossman

et al. 2018

J Virol

170

174

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Venezuelan equine encephalitis virus (VEEV) is a representative member of the New World alphaviruses. It is transmitted by mosquito vectors and causes highly debilitating disease in humans, equides and other vertebrate hosts. Despite a continuous public health threat, very few compounds with anti-VEEV activity in cell culture and in mouse models have been identified to date, and rapid development of virus resistance to some of them has been recorded. In this study, we investigated the possibility of using a modified nucleoside analog, β-D-N(4)-hydroxycytidine (NHC), as an anti-VEEV agent and defined the mechanism of its anti-VEEV activity. The results demonstrate that NHC is a very potent antiviral agent. It affects both the release of genome RNA-containing VEE virions and their infectivity. Both these antiviral activities are determined by the NHC-induced accumulation of mutations in virus-specific RNAs. The antiviral effect is most prominent when NHC is applied early in the infectious process, during amplification of negative and positive strand RNAs in the infected cells. Most importantly, only a low level resistance of VEEV to NHC can be developed, and it requires acquisition and cooperative function of more than one mutation in nsP4. These adaptive mutations are closely located in the same segment of nsP4. Our data suggest that NHC is more potent than ribavirin as an anti-VEEV agent, and likely can be used to treat other alphavirus infections.Venezuelan equine encephalitis virus (VEEV) can cause widespread epidemics among humans and domestic animals. VEEV infections result in severe meningoencephalitis and long-term sequilae. No approved therapeutics exist for treatment of VEEV infections. Our study demonstrates that N-hydroxycytidine (NHC) is a very potent anti-VEEV compound, with the EC being below 1 μM. The mechanism of NHC antiviral activity is based on induction of high mutation rates in the viral genome. Accordingly, NHC treatment affects both the rates of particle release and the particle infectivity. Most importantly, in contrast to most of the anti-alphavirus drugs that are under development, resistance of VEEV to NHC develops very inefficiently. Even low levels of resistance require acquisition of multiple mutations in the gene of VEEV-specific RNA-dependent RNA polymerase, nsP4.

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Characterization of β- d - N ⁴ -Hydroxycytidine as a Novel Inhibitor of Chikungunya Virus

Cited by 76 publications

References 24 publications

Orally Efficacious Broad-Spectrum Ribonucleoside Analog Inhibitor of Influenza and Respiratory Syncytial Viruses

Orally Efficacious Broad-Spectrum Ribonucleoside Analog Inhibitor of Influenza and Respiratory Syncytial Viruses

Selective Inhibition of Enterovirus A Species Members’ Reproduction by Furano[2, 3‐d]pyrimidine Nucleosides Revealed by Antiviral Activity Profiling against (+)ssRNA Viruses

β- d - N ⁴ -Hydroxycytidine Is a Potent Anti-alphavirus Compound That Induces a High Level of Mutations in the Viral Genome

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Characterization of β- d - N 4 -Hydroxycytidine as a Novel Inhibitor of Chikungunya Virus

Cited by 76 publications

References 24 publications

Orally Efficacious Broad-Spectrum Ribonucleoside Analog Inhibitor of Influenza and Respiratory Syncytial Viruses

Orally Efficacious Broad-Spectrum Ribonucleoside Analog Inhibitor of Influenza and Respiratory Syncytial Viruses

Selective Inhibition of Enterovirus A Species Members’ Reproduction by Furano[2, 3‐d]pyrimidine Nucleosides Revealed by Antiviral Activity Profiling against (+)ssRNA Viruses

β- d - N 4 -Hydroxycytidine Is a Potent Anti-alphavirus Compound That Induces a High Level of Mutations in the Viral Genome

Contact Info

Product

Resources

About

Characterization of β- d - N ⁴ -Hydroxycytidine as a Novel Inhibitor of Chikungunya Virus

β- d - N ⁴ -Hydroxycytidine Is a Potent Anti-alphavirus Compound That Induces a High Level of Mutations in the Viral Genome