Format

Send to

Choose Destination
Bioorg Med Chem. 2013 Nov 15;21(22):7222-8. doi: 10.1016/j.bmc.2013.08.023. Epub 2013 Aug 20.

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

Author information

1
Institute for Molecular Virology, University of Minnesota, 18-242 Moos Tower, 515 Delaware Street SE, Minneapolis, MN 55455, USA; Molecular and Cellular Developmental Biology & Genetics Graduate Program, Medical School, University of Minnesota, Minneapolis, MN 55455, USA.

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:

2′,2′-difluoro-2′-deoxycytidine; 2′,2′-difluoro-2′-deoxyuridine; 5,6-Dihydro-5-aza-2′-deoxycytidine; 5-AZC; 5-aza-5,6,-dihydro-2′-deoxycytidine; 5-azacytidine; DMSO; Error catastrophe; KP-1212; Lethal mutagenesis; MOI; NRTI; RNRI; Resveratrol; SD; dFdC; dFdU; dimethylsulfoxide; multiplicity of infection; nucleoside reverse transcriptase inhibitor; ribonucleotide reductase inhibitor; standard deviation

PMID:
24120088
PMCID:
PMC3930610
DOI:
10.1016/j.bmc.2013.08.023
[Indexed for MEDLINE]
Free PMC Article

Publication types, MeSH terms, Substances, Grant support

Publication types

MeSH terms

Substances

Grant support

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center