Anti‐flavivirus Activity of Different Tritylated Pyrimidine and Purine Nucleoside Analogues

McGuigan, Christopher; Serpi, Michaela; Ślusarczyk, Magdalena; Ferrari, Valentina; Pertusati, Fabrizio; Meneghesso, Silvia; Derudas, Marco; Farleigh, Laura; Zanetta, Paola; Bugert, Joachim Jakob

doi:10.1002/open.201500216

Cited by 18 publications

(14 citation statements)

References 31 publications

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“…The selected compounds were first evaluated at a fixed 10 μM concentration for their potential inhibition of ZIKV-induced cytopathic effect in a MTS based TCID 50 assay [ 37 ], using cell lines which are physiologically relevant for ZIKV infection, including HUH7 hepatoma cells [ 38 ], dbtrg cells [ 28 ], and A549 cells, which support Zika virus infection in vitro [ 39 ]. The cell lines used were chosen to reflect the pathogenesis of ZIKV in liver (HUH7) and CNS tissues (dbtrg), in addition to a cell line where the ZIKV strain originally isolated in Uganda in 1947 grows and forms plaques particularly well (A549).…”

Section: Resultsmentioning

confidence: 99%

Novel Nucleoside Analogues as Effective Antiviral Agents for Zika Virus Infections

et al. 2020

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Previously considered a neglected flavivirus, Zika virus has recently emerged as a public health concern due to its ability to spread rapidly and cause severe neurological disorders, such as microcephaly in newborn babies from infected mothers, and Guillain-Barré syndrome in adults. Despite extensive efforts towards the identification of effective therapies, specific antivirals are still not available. As part of ongoing medicinal chemistry studies to identify new antiviral agents, we screened against Zika virus replication in vitro in a targeted internal library of small-molecule agents, comprising both nucleoside and non-nucleoside agents. Among the compounds evaluated, novel aryloxyphosphoramidate prodrugs of the nucleosides 2′-C-methyl-adenosine, 2-CMA, and 7-deaza-2′C-methyl-adenosine, 7-DMA, were found to significantly inhibit the virus-induced cytopathic effect in multiple relevant cell lines. In addition, one of these prodrugs exhibits a synergistic antiviral effect against Zika virus when applied in combination with an indirect antiviral agent, a l-dideoxy bicyclic pyrimidine nucleoside analogue, which potently inhibits vaccinia and measles viruses in vitro by targeting a host pathway. Our findings provide a solid basis for further development of an antiviral therapy for Zika virus infections, possibly exploiting a dual approach combining two different agents, one targeting the viral polymerase (direct-acting antiviral), the second targeting a host-directed autophagy mechanism.

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Section: Resultsmentioning

confidence: 99%

Novel Nucleoside Analogues as Effective Antiviral Agents for Zika Virus Infections

et al. 2020

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“…[ 10 , 33 ]. Trimethyl derivatives of fludarabine have shown strong anti-DENV activity with no toxicity at concentration up to 20 μM [ 34 ], suggesting that reducing toxicity of fludarabine is achievable.…”

Section: Discussionmentioning

confidence: 99%

Fludarabine Inhibits Infection of Zika Virus, SFTS Phlebovirus, and Enterovirus A71

Gao

Wen

et al. 2021

Viruses

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Viral infections are one of the leading causes in human mortality and disease. Broad-spectrum antiviral drugs are a powerful weapon against new and re-emerging viruses. However, viral resistance to existing broad-spectrum antivirals remains a challenge, which demands development of new broad-spectrum therapeutics. In this report, we showed that fludarabine, a fluorinated purine analogue, effectively inhibited infection of RNA viruses, including Zika virus, Severe fever with thrombocytopenia syndrome virus, and Enterovirus A71, with all IC50 values below 1 μM in Vero, BHK21, U251 MG, and HMC3 cells. We observed that fludarabine has shown cytotoxicity to these cells only at high doses indicating it could be safe for future clinical use if approved. In conclusion, this study suggests that fludarabine could be developed as a potential broad-spectrum anti-RNA virus therapeutic agent.

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“… 54 In contrast, several nucleosides with a trityl group at the C3′ position showed micromolar inhibitory activity against DENV and YFV (see below). 78 The observed inactivity of 3′- O -methylated and 3′-dehydroxylated nucleosides could be related to either a strict requirement of the TBEV RdRp active site for a 3′-hydroxyl group to form the appropriate hydrogen bonding interactions with the nucleoside triphosphate molecule, or, to inefficient cellular uptake and metabolism to convert the nucleoside molecule into the corresponding triphosphate form. 46 , 54 …”

Section: Inhibitors Of Flaviviral Ns5 Rdrpmentioning

confidence: 99%

“…In a large-scale cell-based screening campaign of alkylated, silylated, or acylated pyrimidine nucleosides, 2′,5′di- O -trityluridine and 3′,5′di- O -trytiluridine were identified as inhibitors of DENV-2 and YFV replication, showing high antiviral potency and favorable cytotoxicity profiles in Vero cells. 78 , 102 , 103 Substantial antiviral effect against YFV was observed also in 2′-deoxy-3′,5′-di- O -trityluridine and in several 5-halogenated bis-tritylated pyrimidine nucleosides; however, their anti-DENV activity was proven to be weaker. 104 Thymidine or 2′-deoxyuridine congeners of 2′,5′- and 3′,5′-tritylated nucleosides led to the loss of antiflavivirus activity or to increased compound cytotoxicity.…”

Section: Inhibitors Of Flaviviral Ns5 Rdrpmentioning

confidence: 99%

Nucleoside analogs as a rich source of antiviral agents active against arthropod-borne flaviviruses

Eyer

Nencka

Clercq

et al. 2018

Antivir Chem Chemother

118

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Nucleoside analogs represent the largest class of small molecule-based antivirals, which currently form the backbone of chemotherapy of chronic infections caused by HIV, hepatitis B or C viruses, and herpes viruses. High antiviral potency and favorable pharmacokinetics parameters make some nucleoside analogs suitable also for the treatment of acute infections caused by other medically important RNA and DNA viruses. This review summarizes available information on antiviral research of nucleoside analogs against arthropod-borne members of the genus Flavivirus within the family Flaviviridae, being primarily focused on description of nucleoside inhibitors of flaviviral RNA-dependent RNA polymerase, methyltransferase, and helicase/NTPase. Inhibitors of intracellular nucleoside synthesis and newly discovered nucleoside derivatives with high antiflavivirus potency, whose modes of action are currently not completely understood, have drawn attention. Moreover, this review highlights important challenges and complications in nucleoside analog development and suggests possible strategies to overcome these limitations.

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Anti‐flavivirus Activity of Different Tritylated Pyrimidine and Purine Nucleoside Analogues

Cited by 18 publications

References 31 publications

Novel Nucleoside Analogues as Effective Antiviral Agents for Zika Virus Infections

Novel Nucleoside Analogues as Effective Antiviral Agents for Zika Virus Infections

Fludarabine Inhibits Infection of Zika Virus, SFTS Phlebovirus, and Enterovirus A71

Nucleoside analogs as a rich source of antiviral agents active against arthropod-borne flaviviruses

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