Drug Resistance and Drug Combination Features of the Human Immunodeficiency Virus Inhibitor, BCH-10652 [(±)-2′-Deoxy-3′-Oxa-4′-Thiocytidine, dOTC]

Taylor, D.L.; Ahmed, Parvin; Tyms, A. S.; Wood, Lowell; Kelly, Lawrence A.; Chambers, Paul J.; Clarke, JR; Bédard, Jean; Bowlin, Terry L.; Rando, RF

doi:10.1177/095632020001100405

Cited by 35 publications

(25 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Tissue culture selections with (+/-) dOTC generated the mutation M184V, which confers high-level resistance to 3TC, and low-level resistance to both ddI and ddC (Gao et al, 1993;Gu et al, 1992). These findings are also consistent with recent results in which selections were performed with (+/-)dOTC (Taylor et al, 2000). In our studies, a single RT clone after selection contained the mutation K65R in addition to M184V.…”

Section: Discussionsupporting

confidence: 93%

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

Richard

Salomón

Oliveira

et al. 2000

Antivir Chem Chemother

View full text Add to dashboard Cite

The patterns of resistance-conferring mutations that are selected in HIV-1 reverse transcriptase (RT) by the racemates of 2′-dideoxy-3′-oxa-4′-thiocytidine (+/-)dOTC and its fluorinated derivative (+/-)dOTFC were characterized. Genotypic and phenotypic analyses of HIV-1 clinical isolates and HXB2D variants selected with (+/-)dOTC and (+/-)dOTFC were performed in primary cells and in the MT-2 T cell line. HIV-1 variants selected with (+/-)dOTC or (+/-)dOTFC displayed fivefold decreased susceptibility to the respective compounds. A substitution of methionine to valine was identified at position 184 (M184V) in variants selected with (+/-)dOTC. In contrast, a mutation of lysine to arginine at position 65 (K65R) was found in variants selected with (+/-)dOTFC. These patterns of selected mutations differ from those seen with the individual enantiomers. Studies with mutated recombinant HXB2D-M184V and -K65R confirmed that these mutations are important for phenotypic resistance in MT-2 cells. Clinical isolates that display resistance to (-)2′-deoxy-3′-thiacytidine (3TC) also showed cross-resistance to (+/-)dOTC and (+/-)dOTFC. These studies demonstrate that similar genotypes may be selected by the dOTC and dOTFC compounds to those with the structurally related drug 3TC.

show abstract

Section: Discussionsupporting

confidence: 93%

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

Richard

Salomón

Oliveira

et al. 2000

Antivir Chem Chemother

View full text Add to dashboard Cite

show abstract

“…SPD754 is the (Ϫ) enantiomer of 2Ј-deoxy-3Ј-oxa-4Ј-thiocytidine (dOTC or BCH-10652) (5,30). SPD754-TP has been shown to inhibit wild-type HIV type 1 (HIV-1) RT in vitro with a K i of 0.08 M (compared with 0.16 M for lamivudine-TP) (5), and SPD754 showed good activity against HIV-1 isolates in vitro (5,30). SPD754-TP is highly selective for HIV-1 RT, having K i values for HIV-1 RT that are 150-to 3,750-fold lower than those for human DNA polymerases (5).…”

mentioning

confidence: 99%

In Vitro Antiretroviral Activity and In Vitro Toxicity Profile of SPD754, a New Deoxycytidine Nucleoside Reverse Transcriptase Inhibitor for Treatment of Human Immunodeficiency Virus Infection

Allard

Muys

et al. 2006

Antimicrob Agents Chemother

View full text Add to dashboard Cite

Nucleoside reverse transcriptase inhibitors (NRTIs) are the backbone of highly active antiretroviral therapy (HAART) recommended for the treatment of human immunodeficiency virus (HIV) infection (7,20), and the use of NRTI-containing combination therapy has significantly decreased the morbidity and mortality associated with HIV disease in treated patients (18,19). NRTIs share a common mechanism of action. All undergo intracellular activation to the NRTI triphosphate (NRTI-TP) form, after which they compete with endogenous deoxynucleotide triphosphates for binding to the viral reverse transcriptase (RT) enzyme, and incorporation of the monophosphate (MP) into the nascent DNA. Since NRTIs lack a substituent capable of supporting further DNA elongation, the incorporation of the NRTI-MP results in the termination of chain elongation and inhibition of reverse transcription.Many patients whose viral replication is effectively controlled by combination antiretroviral therapy ultimately experience virologic failure because of the development of antiretroviral resistance (for reviews, see references 23 and 24). A 6-year survey of viral genotypes in France found that almost 80% of clinical HIV samples collected until 2002 had mutations conferring resistance to NRTIs (29). Primary infection with resistant strains is also being increasingly recognized as a clinical problem in some countries (10,14,26,31). NRTI resistance results from mutational changes within the RT gene. The resulting resistance mechanisms fall into two main categories (for reviews, see references 4 and 8). One group of RT mutations acts to increase the rate of RT-catalyzed phosphorolysis, i.e., the RT-catalyzed excision of the incorporated NRTI-MP from the chain-terminated DNA. These mutations include M41L, D67N, K70R, L210W, T215Y, and K219Q and are sometimes referred to collectively as thymidine analogue mutations (TAMs). The accumulation of these mutations confers high-level resistance to zidovudine and affects viral sensitivity to other NRTIs, including stavudine, tenofovir, and abacavir (4). The other mechanism by which mutations in RT can cause resistance to NRTIs is by altering the discrimination between deoxynucleoside triphosphate substrates and NRTI-TP inhibitors by the substrate binding site of RT. Examples of such mutations include the M184V mutation, which is found frequently in patients experiencing virologic failure during treatment with lamivudine-containing HAART (6,15). This mutation causes high-level resistance to lamivudine and (in combination with other mutations) reduces sensitivity to didanosine, zalcitabine, and abacavir (32). Other mutations

show abstract

“…Both the (+) and (-)-enantiomers of apricitabine demonstrate potent inhibition of HIV-1 replication, however the (+)-enantiomer demonstrated significant mitochondrial and cellular toxicity in pre-clinical studies that was not observed with the (-) enantiomer Taylor et al, 2000). Racemic conversion of (-)-apricitabine to (+)-apricitabine is not observed in vivo (Holdich et al, 2006).…”

Section: Apricitabinementioning

confidence: 94%

Molecular Pharmacology of Nucleoside and Nucleotide HIV-1 Reverse Transcriptase Inhibitors

Herman¹,

Sluis‐Cremer²

2012

Pharmacology

View full text Add to dashboard Cite

Drug Resistance and Drug Combination Features of the Human Immunodeficiency Virus Inhibitor, BCH-10652 [(±)-2′-Deoxy-3′-Oxa-4′-Thiocytidine, dOTC]

Cited by 35 publications

References 33 publications

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

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

In Vitro Antiretroviral Activity and In Vitro Toxicity Profile of SPD754, a New Deoxycytidine Nucleoside Reverse Transcriptase Inhibitor for Treatment of Human Immunodeficiency Virus Infection

Molecular Pharmacology of Nucleoside and Nucleotide HIV-1 Reverse Transcriptase Inhibitors

Contact Info

Product

Resources

About