Anchimerically Activatable Antiviral ProTides

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

doi:10.1021/acsmedchemlett.7b00277

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 journal › Article › peer-review

14 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 language	English (US)
Pages (from-to)	958-962
Number of pages	5
Journal	ACS Medicinal Chemistry Letters
Volume	8
Issue number	9
DOIs	https://doi.org/10.1021/acsmedchemlett.7b00277
State	Published - 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.

Publisher Copyright:
© 2017 American Chemical Society.

Keywords

Dengue virus
Phosphoramidate
antiviral
pronucleotide

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10.1021/acsmedchemlett.7b00277

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5601376

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title = "Anchimerically Activatable Antiviral ProTides",

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.",

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note = "Funding Information: Funding from the University of Minnesota Foundation and support of A.O. by NIH training grant T32 GM008700 is gratefully acknowledged. Publisher Copyright: {\textcopyright} 2017 American Chemical Society.",

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doi = "10.1021/acsmedchemlett.7b00277",

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AU - Okon, Aniekan

AU - Matos De Souza, Marcos Romário

AU - Shah, Rachit

AU - Amorim, Raquel

AU - Da Costa, Luciana Jesus

AU - Wagner, Carston R.

N1 - Funding Information: Funding from the University of Minnesota Foundation and support of A.O. by NIH training grant T32 GM008700 is gratefully acknowledged. Publisher Copyright: © 2017 American Chemical Society.

PY - 2017/9/14

Y1 - 2017/9/14

N2 - 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.

AB - 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.

KW - Dengue virus

KW - Phosphoramidate

KW - antiviral

KW - pronucleotide

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Anchimerically Activatable Antiviral ProTides

Abstract

Bibliographical note

Keywords

UN SDGs

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