2. Academic Validation
  3. Anchimerically Activatable Antiviral ProTides

Anchimerically Activatable Antiviral ProTides

  • ACS Med Chem Lett. 2017 Aug 14;8(9):958-962. doi: 10.1021/acsmedchemlett.7b00277.
Aniekan Okon 1,  Marcos Romário Matos de Souza 2,  Rachit Shah 1,  Raquel Amorim 2,  Luciana Jesus da Costa 2,  Carston R Wagner 1 1
Affiliations

Affiliations

  • 1 Departments of Medicinal Chemistry and Chemistry, University of Minnesota, Minneapolis, Minnesota 55455, United States.
  • 2 Departamento de Virologia, Instituto de Microbiologia Paulo de Góes, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Rio de Janeiro Brazil.
PMID: 28947944 DOI: 10.1021/acsmedchemlett.7b00277
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.

Keywords

Dengue virus; Phosphoramidate; antiviral; pronucleotide.

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