Anchimerically Activatable Antiviral ProTides

Aniekan Okon, Marcos Romário Matos De Souza, Rachit Shah, Raquel Amorim, Luciana Jesus Da Costa, Carston R Wagner

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

This work describes the synthesis and biological evaluation of an anchimerically activated proTide of 2′-C-β-methylguanosine as an inhibitor of dengue virus 2 (DENV-2). The proTide incorporates a chemically cleavable 2-(methylthio)ethyl moiety and a HINT1 hydrolyzable tryptamine phosphoramidate. Inhibition of DENV-2 replication by proTide 6 was 5-fold greater than the parent nucleoside while displaying no apparent cytotoxicity. Furthermore, we demonstrate with a HINT1 inhibitor that the anti DENV-2 activity of the proTide correlates with the activity of HINT1. Taken together, these results demonstrate that a phosphoramidate based pronucleotide that undergoes an initial nonenzymatic activation step based on anchimeric assistance followed by P-N bond cleavage by HINT1 can be prepared.

Original languageEnglish (US)
Pages (from-to)958-962
Number of pages5
JournalACS Medicinal Chemistry Letters
Volume8
Issue number9
DOIs
StatePublished - Jan 1 2017

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Dengue Virus
Viruses
Antiviral Agents
Cytotoxicity
Virus Replication
Nucleosides
Chemical activation
phosphoramidic acid

Keywords

  • Dengue virus
  • Phosphoramidate
  • antiviral
  • pronucleotide

Cite this

Okon, A., Matos De Souza, M. R., Shah, R., Amorim, R., Da Costa, L. J., & Wagner, C. R. (2017). Anchimerically Activatable Antiviral ProTides. ACS Medicinal Chemistry Letters, 8(9), 958-962. https://doi.org/10.1021/acsmedchemlett.7b00277

Anchimerically Activatable Antiviral ProTides. / Okon, Aniekan; Matos De Souza, Marcos Romário; Shah, Rachit; Amorim, Raquel; Da Costa, Luciana Jesus; Wagner, Carston R.

In: ACS Medicinal Chemistry Letters, Vol. 8, No. 9, 01.01.2017, p. 958-962.

Research output: Contribution to journalArticle

Okon, A, Matos De Souza, MR, Shah, R, Amorim, R, Da Costa, LJ & Wagner, CR 2017, 'Anchimerically Activatable Antiviral ProTides', ACS Medicinal Chemistry Letters, vol. 8, no. 9, pp. 958-962. https://doi.org/10.1021/acsmedchemlett.7b00277
Okon, Aniekan ; Matos De Souza, Marcos Romário ; Shah, Rachit ; Amorim, Raquel ; Da Costa, Luciana Jesus ; Wagner, Carston R. / Anchimerically Activatable Antiviral ProTides. In: ACS Medicinal Chemistry Letters. 2017 ; Vol. 8, No. 9. pp. 958-962.
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