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

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

^*Corresponding author for this work

Medical Social Sciences

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

23 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

Keywords

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

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

UN SDGs

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

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10.1016/j.bmc.2013.08.023

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@article{d47bb4fb4f9c4116953a94ace4957191,

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 Brittany} 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.",

year = "2013",

month = nov,

day = "15",

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

language = "English (US)",

volume = "21",

pages = "7222--7228",

journal = "Bioorganic and Medicinal Chemistry",

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T1 - 5,6-Dihydro-5-aza-2′-deoxycytidine potentiates the anti-HIV-1 activity of ribonucleotide reductase inhibitors

AU - Rawson, Jonathan M.

AU - Heineman, Richard H.

AU - Beach, Lauren Brittany

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.

KW - 5,6-Dihydro-5-aza-2′-deoxycytidine

KW - Error catastrophe

KW - KP-1212

KW - Lethal mutagenesis

KW - Resveratrol

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IS - 22

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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