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 journalArticle

16 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

Keywords

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

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