Abstract |
The potent antiretroviral 4'-ethynyl-2-fluoro-2'-deoxyadenosine ( EFdA) is a promising experimental agent for treating HIV infection. Pre-steady-state kinetics were used to characterize the interaction of EFdA- triphosphate ( EFdA-TP) with human mitochondrial DNA polymerase γ (Pol γ) to assess the potential for toxicity. Pol γ incorporated EFdA-TP 4,300-fold less efficiently than dATP, with an excision rate similar to ddATP. This strongly indicates EFdA is a poor Pol γ substrate, suggesting minimal Pol γ-mediated toxicity, although this should be examined under clinical settings.
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Authors | Christal D Sohl, Kamlendra Singh, Rajesh Kasiviswanathan, William C Copeland, Hiroaki Mitsuya, Stefan G Sarafianos, Karen S Anderson |
Journal | Antimicrobial agents and chemotherapy
(Antimicrob Agents Chemother)
Vol. 56
Issue 3
Pg. 1630-4
(Mar 2012)
ISSN: 1098-6596 [Electronic] United States |
PMID | 22155823
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural)
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Chemical References |
- Deoxyadenosines
- Mitochondrial Proteins
- Reverse Transcriptase Inhibitors
- HIV Reverse Transcriptase
- DNA Polymerase gamma
- DNA-Directed DNA Polymerase
- islatravir
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Topics |
- Base Sequence
- DNA Polymerase gamma
- DNA-Directed DNA Polymerase
(metabolism)
- Deoxyadenosines
(metabolism, pharmacology, toxicity)
- HIV Reverse Transcriptase
(antagonists & inhibitors, metabolism)
- HIV-1
(drug effects, physiology)
- Humans
- Kinetics
- Mitochondria
(drug effects, metabolism)
- Mitochondrial Proteins
(metabolism)
- Models, Molecular
- Molecular Sequence Data
- Reverse Transcriptase Inhibitors
(metabolism, pharmacology, toxicity)
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