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

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

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

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