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Anchimerically Activatable Antiviral ProTides.

ABSTRACT: This work describes the synthesis and biological evaluation of an anchimerically activated proTide of 2'-C-?-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.

SUBMITTER: Okon A

PROVIDER: S-EPMC5601376 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Anchimerically Activatable Antiviral ProTides.

Okon Aniekan A Matos de Souza Marcos Romário MR Shah Rachit R Amorim Raquel R da Costa Luciana Jesus LJ Wagner Carston R CR

ACS medicinal chemistry letters 20170814 9

This work describes the synthesis and biological evaluation of an anchimerically activated proTide of 2'-<i>C</i>-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 <b>6</b> was 5-fold greater than the parent nucleoside while displaying no apparent cytotoxicity. Furthermore, we demonstrate with a HINT1 inhibitor tha ...[more]

PMID: 28947944

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