5,6-Dihydro-5-aza-2′-deoxycytidine potentiates the anti-HIV-1 activity of ribonucleotide reductase inhibitors

Jonathan M. Rawson; Richard H. Heineman; Lauren B. Beach; Jessica L. Martin; Erica K. Schnettler; Michael J. Dapp; Steven E. Patterson; Louis M. Mansky

doi:10.1016/j.bmc.2013.08.023

5,6-Dihydro-5-aza-2′-deoxycytidine potentiates the anti-HIV-1 activity of ribonucleotide reductase inhibitors

Jonathan M. Rawson
, Richard H. Heineman
, Lauren B. Beach
, Jessica L. Martin
, Erica K. Schnettler
, Michael J. Dapp
, Steven E. Patterson
, Louis M. Mansky

Research output: Contribution to journal › Article › peer-review

25 Scopus citations

Abstract

The nucleoside analog 5,6-dihydro-5-aza-2′-deoxycytidine (KP-1212) has been investigated as a first-in-class lethal mutagen of human immunodeficiency virus type-1 (HIV-1). Since a prodrug monotherapy did not reduce viral loads in Phase II clinical trials, we tested if ribonucleotide reductase inhibitors (RNRIs) combined with KP-1212 would improve antiviral activity. KP-1212 potentiated the activity of gemcitabine and resveratrol and simultaneously increased the viral mutant frequency. G-to-C mutations predominated with the KP-1212-resveratrol combination. These observations represent the first demonstration of a mild anti-HIV-1 mutagen potentiating the antiretroviral activity of RNRIs and encourage the clinical translation of enhanced viral mutagenesis in treating HIV-1 infection.

Original language	English (US)
Pages (from-to)	7222-7228
Number of pages	7
Journal	Bioorganic and Medicinal Chemistry
Volume	21
Issue number	22
DOIs	https://doi.org/10.1016/j.bmc.2013.08.023
State	Published - Nov 15 2013

Bibliographical note

Funding Information:
This research was supported by NIH grants R01 GM56615 and R21 AI96937 . J.M.R. was supported by the Institute for Molecular Virology Training Program (NIH grant T32AI83196 ); R.H.H. was supported by the MinnCResT Program (NIH grant T32DE007288 ); L.B.B. was supported by NIH grant F31DA030249 ; J.L.M. was supported by a University of Minnesota Basic Sciences PhD Graduate Programs Council Fellowship; M.J.D. was supported by NIH grant T32DA007097 . Combustion analysis of KP-1212 and gemcitabine was performed by Atlantic Microlab, Inc. (Norcross, GA). The authors would like to thank Laurent Bonnac for performing 1 H NMR of KP-1212 and Cavan Reilly for suggestions regarding statistical tests and procedures.

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This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

5,6-Dihydro-5-aza-2′-deoxycytidine
Error catastrophe
KP-1212
Lethal mutagenesis
Resveratrol

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10.1016/j.bmc.2013.08.023

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title = "5,6-Dihydro-5-aza-2′-deoxycytidine potentiates the anti-HIV-1 activity of ribonucleotide reductase inhibitors",

abstract = "The nucleoside analog 5,6-dihydro-5-aza-2′-deoxycytidine (KP-1212) has been investigated as a first-in-class lethal mutagen of human immunodeficiency virus type-1 (HIV-1). Since a prodrug monotherapy did not reduce viral loads in Phase II clinical trials, we tested if ribonucleotide reductase inhibitors (RNRIs) combined with KP-1212 would improve antiviral activity. KP-1212 potentiated the activity of gemcitabine and resveratrol and simultaneously increased the viral mutant frequency. G-to-C mutations predominated with the KP-1212-resveratrol combination. These observations represent the first demonstration of a mild anti-HIV-1 mutagen potentiating the antiretroviral activity of RNRIs and encourage the clinical translation of enhanced viral mutagenesis in treating HIV-1 infection.",

keywords = "5,6-Dihydro-5-aza-2′-deoxycytidine, Error catastrophe, KP-1212, Lethal mutagenesis, Resveratrol",

author = "Rawson, \{Jonathan M.\} and Heineman, \{Richard H.\} and Beach, \{Lauren B.\} and Martin, \{Jessica L.\} and Schnettler, \{Erica K.\} and Dapp, \{Michael J.\} and Patterson, \{Steven E.\} and Mansky, \{Louis M.\}",

note = "Funding Information: This research was supported by NIH grants R01 GM56615 and R21 AI96937 . J.M.R. was supported by the Institute for Molecular Virology Training Program (NIH grant T32AI83196 ); R.H.H. was supported by the MinnCResT Program (NIH grant T32DE007288 ); L.B.B. was supported by NIH grant F31DA030249 ; J.L.M. was supported by a University of Minnesota Basic Sciences PhD Graduate Programs Council Fellowship; M.J.D. was supported by NIH grant T32DA007097 . Combustion analysis of KP-1212 and gemcitabine was performed by Atlantic Microlab, Inc. (Norcross, GA). The authors would like to thank Laurent Bonnac for performing 1 H NMR of KP-1212 and Cavan Reilly for suggestions regarding statistical tests and procedures.",

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doi = "10.1016/j.bmc.2013.08.023",

language = "English (US)",

volume = "21",

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AU - Rawson, Jonathan M.

AU - Heineman, Richard H.

AU - Beach, Lauren B.

AU - Martin, Jessica L.

AU - Schnettler, Erica K.

AU - Dapp, Michael J.

AU - Patterson, Steven E.

AU - Mansky, Louis M.

N1 - Funding Information: This research was supported by NIH grants R01 GM56615 and R21 AI96937 . J.M.R. was supported by the Institute for Molecular Virology Training Program (NIH grant T32AI83196 ); R.H.H. was supported by the MinnCResT Program (NIH grant T32DE007288 ); L.B.B. was supported by NIH grant F31DA030249 ; J.L.M. was supported by a University of Minnesota Basic Sciences PhD Graduate Programs Council Fellowship; M.J.D. was supported by NIH grant T32DA007097 . Combustion analysis of KP-1212 and gemcitabine was performed by Atlantic Microlab, Inc. (Norcross, GA). The authors would like to thank Laurent Bonnac for performing 1 H NMR of KP-1212 and Cavan Reilly for suggestions regarding statistical tests and procedures.

PY - 2013/11/15

Y1 - 2013/11/15

N2 - The nucleoside analog 5,6-dihydro-5-aza-2′-deoxycytidine (KP-1212) has been investigated as a first-in-class lethal mutagen of human immunodeficiency virus type-1 (HIV-1). Since a prodrug monotherapy did not reduce viral loads in Phase II clinical trials, we tested if ribonucleotide reductase inhibitors (RNRIs) combined with KP-1212 would improve antiviral activity. KP-1212 potentiated the activity of gemcitabine and resveratrol and simultaneously increased the viral mutant frequency. G-to-C mutations predominated with the KP-1212-resveratrol combination. These observations represent the first demonstration of a mild anti-HIV-1 mutagen potentiating the antiretroviral activity of RNRIs and encourage the clinical translation of enhanced viral mutagenesis in treating HIV-1 infection.

AB - The nucleoside analog 5,6-dihydro-5-aza-2′-deoxycytidine (KP-1212) has been investigated as a first-in-class lethal mutagen of human immunodeficiency virus type-1 (HIV-1). Since a prodrug monotherapy did not reduce viral loads in Phase II clinical trials, we tested if ribonucleotide reductase inhibitors (RNRIs) combined with KP-1212 would improve antiviral activity. KP-1212 potentiated the activity of gemcitabine and resveratrol and simultaneously increased the viral mutant frequency. G-to-C mutations predominated with the KP-1212-resveratrol combination. These observations represent the first demonstration of a mild anti-HIV-1 mutagen potentiating the antiretroviral activity of RNRIs and encourage the clinical translation of enhanced viral mutagenesis in treating HIV-1 infection.

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KW - KP-1212

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KW - Resveratrol

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ER -

5,6-Dihydro-5-aza-2′-deoxycytidine potentiates the anti-HIV-1 activity of ribonucleotide reductase inhibitors

Abstract

Bibliographical note

UN SDGs

Keywords

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