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 journalArticlepeer-review

10 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 - Sep 14 2017

Bibliographical note

Funding Information:
Funding from the University of Minnesota Foundation and support of A.O. by NIH training grant T32 GM008700 is gratefully acknowledged.

Keywords

  • Dengue virus
  • Phosphoramidate
  • antiviral
  • pronucleotide

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