Selection of Resistance-Conferring Mutations in HIV-1 by the Nucleoside Reverse Transcriptase Inhibitors (+/-)dOTC and (+/-)dOTFC

Richard, Nathalie; Salomón, Horacio; Oliveira, Maureen; Rando, Robert F.; Mansour, Tarek S.; Gu, Zhengxian; Wainberg, Mark A.

doi:10.1177/095632020001100602

Cited by 8 publications

(2 citation statements)

References 25 publications

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“…We have now shown that apricitabine-TP effectively retained its chain-termination activity against WT RT, L74V RT (resistant to ddI and abacavir), M184V RT and K103N RT (resistant to nonnucleoside reverse transcriptase inhibitors). K65R RT had decreased susceptibility to apricitabine-TP compared to WT RT, as has been described for K65R-containing viruses (Richard et al, 2000).…”

supporting

confidence: 72%

Kinetics of Inhibition of HIV Type 1 Reverse Transcriptase-Bearing NRTI-associated Mutations by Apricitabine Triphosphate

Frankel

Coutsinos

et al. 2007

Antivir Chem Chemother

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We wished to investigate the effects of various mutations in HIV-1 reverse transcriptase (RT) on biochemical inhibition by the active form of a novel nucleoside termed apricitabine. Accordingly, we studied the efficiency of chain-termination mediated by apricitabine triphosphate (TP) in cellfree assays that used either recombinant wild-type or mutated RTs. We also performed steady-statekinetics and primer-unblocking assays. Subtype C RTs were also analysed. The results showed that the K65R mutation in RT caused reductions in the efficiency of chain-termination of apricitabine-TP by increasing its K i . However, K65R did not affect rates of primer unblocking for apricitabine-TP. No significant differences were found between subtype C and subtype B RTs with regard to any of the parameters studied. Other mutations such as M184V, L74V and K103N had no effect on the efficiency of chain termination by apricitabine-TP. Thus, the mechanism of reduced susceptibility to apricitabine of viruses containing K65R in RT seems to be mediated exclusively through a reduction in binding or incorporation of apricitabine-TP. Unlike some other nucleoside analogues, increased excision of incorporated apricitabine does not seem to be a cause of resistance to apricitabine.

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supporting

confidence: 72%

Kinetics of Inhibition of HIV Type 1 Reverse Transcriptase-Bearing NRTI-associated Mutations by Apricitabine Triphosphate

Frankel

Coutsinos

et al. 2007

Antivir Chem Chemother

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“…Reverset (D-d4FC) has demonstrated activity against wildtype HIV-1 and HIV-2 as well as virus resistant to lamivudine (3TC), zidovudine (AZT) and other NRTIs [12,13]. SPD-754 is the (-) enantiomer of a previously studied compound, dOTC, which displayed unacceptable toxicity, however SPD-754 appears to be better tolerated [11,14]. Racivir, (±)-FTC, a 50:50 mixture of two β-enantiomers of FTC, displays greater activity than (-)-FTC in vitro against HIV-1 and HBV [11,15].…”

Section: Human Immunodeficiency Virus (Hiv)mentioning

confidence: 99%

Recent Advances in Antiviral Nucleoside and Nucleotide Therapeutics

Simons

Wu²,

Htar³

2005

CTMC

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Recent developments in nucleoside/nucleotide therapeutics and antiviral drug targets are described covering progress in the development of nucleoside/nucleotide mimetics for the treatment of influenza virus, human immunodeficiency virus type 1, hepatitis B and C virus, herpes virus infections; including herpes simplex virus, cytomegalovirus and varicella zoster virus infections, and the highly pathogenic poxviruses (variola, vaccinia and monkey pox) and filoviruses (Ebola and Marburg).

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Nucleoside and nucleotide inhibitors of HIV-1 replication

Vivet-Boudou

Didierjean

Isel

et al. 2006

Cell. Mol. Life Sci.

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HIV-1 reverse transcriptase (RT) is one of the main targets for antiviral therapy. Two classes of RT inhibitors can be distinguished: those that are nucleoside or nucleotide analogues (sharing the common NRTIs abbreviation) and those that are not. This review focuses on the NRTIs, which are highly efficient in slowing down viral replication and are used in combination regimens. Unfortunately, the current inhibitors do not completely suppress viral replication and due to the high capacity of adaptation of HIV, allow the selection of drug-resistant viruses. Resistance mechanisms to NRTIs have been extensively investigated and can be divided into two types: improved discrimination of a nucleotide analogue relative to the natural substrate or increased phosphorolytic cleavage of an analogue-blocked primer. This knowledge is important both for the development of new drugs designed to target resistant strains and for the development of new antiviral strategies. The NRTIs currently in clinical trials and new developments in this area are also reviewed.

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Selection of Resistance-Conferring Mutations in HIV-1 by the Nucleoside Reverse Transcriptase Inhibitors (+/-)dOTC and (+/-)dOTFC

Cited by 8 publications

References 25 publications

Kinetics of Inhibition of HIV Type 1 Reverse Transcriptase-Bearing NRTI-associated Mutations by Apricitabine Triphosphate

Kinetics of Inhibition of HIV Type 1 Reverse Transcriptase-Bearing NRTI-associated Mutations by Apricitabine Triphosphate

Recent Advances in Antiviral Nucleoside and Nucleotide Therapeutics

Nucleoside and nucleotide inhibitors of HIV-1 replication

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