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.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, N.I.H., Intramural
MeSH terms
-
Base Sequence
-
DNA Polymerase gamma
-
DNA-Directed DNA Polymerase / metabolism*
-
Deoxyadenosines / metabolism
-
Deoxyadenosines / pharmacology*
-
Deoxyadenosines / toxicity
-
HIV Reverse Transcriptase / antagonists & inhibitors*
-
HIV Reverse Transcriptase / metabolism
-
HIV-1 / drug effects*
-
HIV-1 / physiology
-
Humans
-
Kinetics
-
Mitochondria / drug effects*
-
Mitochondria / metabolism
-
Mitochondrial Proteins / metabolism*
-
Models, Molecular
-
Molecular Sequence Data
-
Reverse Transcriptase Inhibitors / metabolism
-
Reverse Transcriptase Inhibitors / pharmacology*
-
Reverse Transcriptase Inhibitors / toxicity
Substances
-
Deoxyadenosines
-
Mitochondrial Proteins
-
Reverse Transcriptase Inhibitors
-
HIV Reverse Transcriptase
-
DNA Polymerase gamma
-
DNA-Directed DNA Polymerase
-
islatravir