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 journalArticlepeer-review

17 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 languageEnglish (US)
Pages (from-to)7222-7228
Number of pages7
JournalBioorganic and Medicinal Chemistry
Volume21
Issue number22
DOIs
StatePublished - 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.

Copyright:
Copyright 2013 Elsevier B.V., All rights reserved.

Keywords

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

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