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

5 Scopus citations

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

Keywords

  • Dengue virus
  • Phosphoramidate
  • antiviral
  • pronucleotide

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  • 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