Structure-activity relationship of uridine-based nucleoside phosphoramidate prodrugs for inhibition of dengue virus RNA-dependent RNA polymerase

Wang, Gang; Lim, Siew Pheng; Chen, Yen-Liang; Hunziker, Jürg; Rao, Ranga; Gu, Feng; Seh, Cheah Chen; Ghafar, Nahdiyah Abdul; Xu, Haoying; Chan, Katherine; Lin, Xiaodong; Saunders, Oliver L.; Fenaux, Martijn; Zhong, Weidong; Shi, Pei Yong; Yokokawa, Fumiaki

doi:10.1016/j.bmcl.2018.04.069

Cited by 21 publications

(15 citation statements)

References 23 publications

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“…Synthesis of 2d and 2e is shown is Scheme , starting from the known 1c . The 2′ and 3′-hydroxyls of 1c were protected with cyclopentylidene, and the 5′-hydroxyl was converted to the 5′-iodide.…”

Section: Resultsmentioning

confidence: 99%

“…To a solution of benzoylated nucleoside 6 (50 g, 86 mmol) in DMF at 0 °C were added PMBCl (16 g, 0.1 mol) and K 2 CO 3 (17.8 g, 0.13 mol). After stirring at rt for 12 h, the reaction mixture was quenched with water (100 mL) and extracted with EtOAc (3 × 200 mL).…”

Section: Methodsmentioning

confidence: 99%

“…A solution of TsOH·H 2 O (0.7 g, 3.7 mmol), 1,1-dimethoxycyclopentane (19.3 g, 148.5 mmol), and 2′-ethynyluridine 1c (10.0 g, 37.1 mmol) in DCE (100 mL) was stirred at 50 °C overnight. The reaction mixture was neutralized with Et 3 N and concentrated.…”

Section: Methodsmentioning

confidence: 99%

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Synthesis and Anti-HCV Activities of 4′-Fluoro-2′-Substituted Uridine Triphosphates and Nucleotide Prodrugs: Discovery of 4′-Fluoro-2′-C-methyluridine 5′-Phosphoramidate Prodrug (AL-335) for the Treatment of Hepatitis C Infection

et al. 2019

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We report the synthesis and biological evaluation of a series of 4′-fluoro-2′-C-substituted uridines. Triphosphates of the uridine analogues exhibited a potent inhibition of hepatitis C virus (HCV) NS5B polymerase with IC50 values as low as 27 nM. In an HCV subgenomic replicon assay, the phosphoramidate prodrugs of these uridine analogues demonstrated a very potent activity with EC50 values as low as 20 nM. A lead compound AL-335 (53) demonstrated high levels of the nucleoside triphosphate in vitro in primary human hepatocytes and Huh-7 cells as well as in dog liver following a single oral dose. Compound 53 was selected for the clinical development where it showed promising results in phase 1 and 2 trials.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Synthesis and Anti-HCV Activities of 4′-Fluoro-2′-Substituted Uridine Triphosphates and Nucleotide Prodrugs: Discovery of 4′-Fluoro-2′-C-methyluridine 5′-Phosphoramidate Prodrug (AL-335) for the Treatment of Hepatitis C Infection

et al. 2019

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“…Also included were new ProTides of 2′- C -ethynyl- and 2′- C -ethenyluridine. The 2′- C -ethynyl ribosyl triphosphates are known sub-μM inhibitors of flavivirus RdRPs [31,45], and we prepared the new 2′- C -ethenyluridine ProTide to probe the active site of the RdRP and the metabolic consequences of further modification of the 2′- C- β position. A 5-fluorouridine ProTide was included in our set of analogues to test inhibition by lethal mutagenesis, although toxicity of mutagenic nucleoside analogues is typically prohibitive of clinical applications.…”

Section: Resultsmentioning

confidence: 99%

Activity of Selected Nucleoside Analogue ProTides against Zika Virus in Human Neural Stem Cells

Bernatchez

Coste

Beck

et al. 2019

Viruses

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Zika virus (ZIKV), an emerging flavivirus that causes neurodevelopmental impairment to fetuses and has been linked to Guillain-Barré syndrome continues to threaten global health due to the absence of targeted prophylaxis or treatment. Nucleoside analogues are good examples of efficient anti-viral inhibitors, and prodrug strategies using phosphate masking groups (ProTides) have been employed to improve the bioavailability of ribonucleoside analogues. Here, we synthesized and tested a small library of 13 ProTides against ZIKV in human neural stem cells. Strong activity was observed for 2′-C-methyluridine and 2′-C-ethynyluridine ProTides with an aryloxyl phosphoramidate masking group. Substitution of a 2-(methylthio) ethyl phosphoramidate for the aryloxyl phosphoramidate ProTide group of 2′-C-methyluridine completely abolished antiviral activity of the compound. The aryloxyl phosphoramidate ProTide of 2′-C-methyluridine outperformed the hepatitis C virus (HCV) drug sofosbuvir in suppression of viral titers and protection from cytopathic effect, while the former compound’s triphosphate active metabolite was better incorporated by purified ZIKV NS5 polymerase over time. These findings suggest both a nucleobase and ProTide group bias for the anti-ZIKV activity of nucleoside analogue ProTides in a disease-relevant cell model.

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“…Also included are new ProTides of 2′- C -ethynyl- and 2′- C -ethenyluridine. 2′- C -ethynyl ribosyl triphosphates are known sub-μΜ inhibitors of flavivirus RdRPs [31,43], and we prepared the new 2′- C -ethenyluridine ProTide to probe the active site of the RdRP and the metabolic consequences of further modification of the 2 ′-C-β position. A 5-fluorouridine ProTide was included in our set of analogues to test inhibition by lethal mutagenesis, although toxicity of mutagenic nucleoside analogues is typically prohibitive of clinical applications.…”

Section: Resultsmentioning

confidence: 99%

Activity of Selected Nucleoside Analogue ProTides against Zika Virus in Human Neural Stem Cells

Bernatchez

Coste

Beck

et al. 2019

Preprint

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Zika virus (ZIKV), an emerging flavivirus which causes neurodevelopmental impairment 22 to fetuses and has been linked to Guillain-Barré syndrome, continues to threaten global health due 23 to the absence of targeted prophylaxis or treatment. Nucleoside analogues are good examples of 24 efficient anti-viral inhibitors, and prodrug strategies using phosphate masking groups (ProTides) 25 have been employed to improve the bioavailability of ribonucleoside analogues. Here, we 26 synthesized and tested a library of 13 ProTides against ZIKV in human neural stem cells. Strong 27 activity was observed for 2'-C-methyluridine and 2'-C-ethynyluridine ProTides with an aryloxyl 28 phosphoramidate masking group. Conversion of the aryloxyl phosphoramidate ProTide group of 29 2'-C-methyluridine to a 2-(methylthio)ethyl phosphoramidate completely abolished antiviral 30 activity of the compound. The aryloxyl phosphoramidate ProTide of 2'-C-methyluridine 31 outperformed the hepatitis C virus (HCV) drug sofosbuvir in suppression of viral titers and 32 protection from cytopathic effect, while the former compound's triphosphate active metabolite was 33 better incorporated by purified ZIKV NS5 polymerase over time. Molecular superpositioning 34 revealed different orientations of residues opposite the 2'-fluoro group of sofosbuvir. These findings 35 suggest both a nucleobase and ProTide group bias for the anti-ZIKV activity of nucleoside analogue 36 ProTides in a disease-relevant cell model. 37 38 cells, RNA-dependent RNA polymerase 39 40 1. Introduction 41The explosive spread of Zika virus (ZIKV) during the 2015-2016 epidemics in Latin America 42 attracted worldwide attention to this previously neglected disease. The lack of effective vaccines or 43 small molecules to prevent or treat this infection remains a cause for concern and emphasizes the 44 urgent need for new therapeutic options [1]. ZIKV, an emerging flavivirus infection, causes several 48 manifestations of the disease, and in rare cases, ZIKV infection has been linked to the 49 neuroinflammatory Guillain-Barré syndrome [2]. 50 Viral polymerases remain attractive drug targets for the development of selective antiviral 51 therapies [3-5]. Generally, clinically-approved inhibitors that target these proteins fall into two broad 52 classes [6,7]. The first class consists of nucleoside analogues that mimic the natural substrate of the 53 enzyme. Upon analogue incorporation by the virally-encoded polymerase, DNA or RNA synthesis 54 is abrogated by preventing further nucleotide incorporation (chain termination), thereby arresting 55 viral replication. The second class is known as non-nucleoside inhibitors, which bind allosterically 56 and arrest viral nucleic acid synthesis by distorting the polymerase active site geometry to interfere 57 with nucleotide binding or nucleotide incorporation. 58 A common prodrug strategy used for antiviral ribonucleoside analogues involves the chemical 59 synthesis of nucleoside analogue monophosphates with metabolically-removable masking groups 60 [8...

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Structure-activity relationship of uridine-based nucleoside phosphoramidate prodrugs for inhibition of dengue virus RNA-dependent RNA polymerase

Cited by 21 publications

References 23 publications

Synthesis and Anti-HCV Activities of 4′-Fluoro-2′-Substituted Uridine Triphosphates and Nucleotide Prodrugs: Discovery of 4′-Fluoro-2′-C-methyluridine 5′-Phosphoramidate Prodrug (AL-335) for the Treatment of Hepatitis C Infection

Synthesis and Anti-HCV Activities of 4′-Fluoro-2′-Substituted Uridine Triphosphates and Nucleotide Prodrugs: Discovery of 4′-Fluoro-2′-C-methyluridine 5′-Phosphoramidate Prodrug (AL-335) for the Treatment of Hepatitis C Infection

Activity of Selected Nucleoside Analogue ProTides against Zika Virus in Human Neural Stem Cells

Activity of Selected Nucleoside Analogue ProTides against Zika Virus in Human Neural Stem Cells

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