Cytosine deoxyribonucleoside anti-HIV analogues: a small chemical substitution allows relevant activities

Scaglione, Francesco; Berrino, Liberato

doi:10.1016/j.ijantimicag.2011.11.013

Cited by 8 publications

(7 citation statements)

References 59 publications

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“…Although both FNC and 3TC showed high cross-resistance to HIV-1 LAI-M184V , FNC still showed strong activity at nontoxic concentration (26.75 nM) whereas 3TC lost the activity (EC 50 >800 µM) (Table 3). Our results showed that the EC 50 values of FNC were 2000 to 11000-fold lower compared to 3TC and those of FTC were 0.8 to 69-fold lower compared to 3TC [34]. Similarly, FNC showed stronger inhibition on HIV-1 and HIV-2 than 3TC and FTC, which implies a relatively low clinical doses of FNC may be sufficient for viral control and in turn trigger fewer side-effects.…”

Section: Discussionmentioning

confidence: 57%

“…FNC was highly effective on lab-adaptive strains and clinical isolated strains with EC 50 s lower than single-nanomolar. This indicates that FNC has better anti-HIV-1 activity than 3TC and FTC [34], [37], [38]. In mechanism study, FNC shown comparable activity in inhibiting reverse transcription products with the dosage only one-thousandth of 3TC (Figure 2).…”

Section: Discussionmentioning

confidence: 93%

“…FTC is a NRTI structurally related to 3TC and shares comparable efficacy against HBV. However, it has a quite similar resistance profiles with 3TC [34]. AIDS requires long-term medication and necessitates the drug regimens to have low drug resistance and require less frequent administration.…”

Section: Discussionmentioning

confidence: 99%

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Azvudine, A Novel Nucleoside Reverse Transcriptase Inhibitor Showed Good Drug Combination Features and Better Inhibition on Drug-Resistant Strains than Lamivudine In Vitro

et al. 2014

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Azvudine is a novel nucleoside reverse transcriptase inhibitor with antiviral activity on human immunodeficiency virus, hepatitis B virus and hepatitis C virus. Here we reported the in vitro activity of azvudine against HIV-1 and HIV-2 when used alone or in combination with other antiretroviral drugs and its drug resistance features. Azvudine exerted highly potent inhibition on HIV-1 (EC50s ranging from 0.03 to 6.92 nM) and HIV-2 (EC50s ranging from 0.018 to 0.025 nM). It also showed synergism in combination with six approved anti-HIV drugs on both C8166 and PBMC. In combination assay, the concentrations of azvudine used were 1000 or 500 fold lower than other drugs. Azvudine also showed potent inhibition on NRTI-resistant strains (L74V and T69N). Although M184V caused 250 fold reduction in susceptibility, azvudine remained active at nanomolar range. In in vitro induced resistant assay, the frequency of M184I mutation increased with induction time which suggests M184I as the key mutation in azvudine treatment. As control, lamivudine treatment resulted in a higher frequency of M184I/V given the same induction time and higher occurrence of M184V was found. Molecular modeling analysis suggests that steric hindrance is more pronounced in mutant M184I than M184V due to the azido group of azvudine. The present data demonstrates the potential of azvudine as a complementary drug to current anti-HIV drugs. M184I should be the key mutation, however, azvudine still remains active on HIV-1LAI-M184V at nanomolar range.

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Section: Discussionmentioning

confidence: 57%

Section: Discussionmentioning

confidence: 93%

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Azvudine, A Novel Nucleoside Reverse Transcriptase Inhibitor Showed Good Drug Combination Features and Better Inhibition on Drug-Resistant Strains than Lamivudine In Vitro

et al. 2014

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“…The latest antiretroviral treatment guidelines of the US Department of Health and Human Services [3] and the World Health Organization [4] consider lamivudine and emtricitabine to be equivalent and interchangeable from a clinical and programmatic perspective. However, inferior virological efficacy of lamivudine has been suggested based on limited data from early in-vitro studies [5] , [6] and this presumption of inferiority has been applied to recent cost-effectiveness analyses [7] . There is therefore uncertainly regarding the clinical comparability of these two drugs.…”

Section: Introductionmentioning

confidence: 99%

Comparative Efficacy of Lamivudine and Emtricitabine: A Systematic Review and Meta-Analysis of Randomized Trials

et al. 2013

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IntroductionLamivudine and emtricitabine are considered equivalent by several guidelines, but evidence of comparable efficacy is conflicting.MethodsWe searched two databases up to June 30 2013 to identify randomized and quasi-randomized trials in which lamivudine and emtricitabine were used as part of combination antiretroviral therapy for treatment-naïve or experienced HIV-positive adult patients. We only included trials where partner drugs in the regimen were identical or could be considered to be comparable. We allowed for comparisons between tenofovir and abacavir provided the study population did not begin treatment with a viral load >100,000 copies/ml.Results12 trials contributed 15 different randomized comparisons providing data on 2251 patients receiving lamivudine and 2662 patients receiving emtricitabine. Treatment success was not significantly different in any of the 12 trials. In the three trials that directly compared lamivudine and emtricitabine, the relative risk for achieving treatment success was non-significant (RR 1.03 95%CI 0.96-1.10). For all trials combined, the pooled relative risk for treatment success was not significantly different (RR 1.00, 95%CI 0.97–1.02). No heterogeneity was observed (I 2 = 0). Similarly, there was no difference in the pooled relative risk for treatment failure (RR 1.08, 95%CI 0.94–1.22, I 2 = 3.4%).ConclusionsThe findings of this systematic review suggest that lamivudine and emtricitabine are clinically equivalent.

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“…Explanation is probably rather complex as these polymorphisms do not affect the level of transcription or translation. ABC C4 is also important in antiretroviral therapy, as its substrates include nucleotide analogs effi ciently used as therapeutics, e.g., 2 ′ ,3 ′ -dideoxy-3 ′ -thiacytidine (lamivudine) (73) . A polymorphism T4131G in 3 ′ UTR was associated with a desirable 20 % elevated concentration of anti-HIV drug lamivudine in lymphocytes and probably caused by altered splicing and in turn reduced function or expression of this protein (74) .…”

Section: Abc C4mentioning

confidence: 99%

Multidrug resistance-associated ABC transporters – too much of one thing, good for nothing

Procházková

Lánová

Pachernı́k

2012

BioMolecular Concepts

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Overexpression of ATP-binding cassette (ABC) transporters in cancer cells results in multidrug resistance (MDR) which leads to unsuccessful chemotherapy. The most important MDR-associated members of ABC superfamily are ABC B1/P-glycoprotein/MDR1, ABC C1/multidrug resistance associated protein 1 (MRP1), and ABC G2/BCRP. This study is not only focused on function, substrates, and localization of these popular proteins but also on other ABC C family members such as ABC C2-6/MRP2-6 and ABC C7/CFTR. Current research is mainly oriented on the cancer-promoting role of these proteins, but important lessons could also be learned from the physiological roles of these proteins or from polymorphisms affecting their function. Thorough knowledge of structure and detailed mechanism of efflux can aid in the discovery of new chemotherapy targets in the future. Although the best way on how to deal with MDR would be to prevent its development, we describe some new promising strategies on how to conquer both inherited and induced MDRs.

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Cytosine deoxyribonucleoside anti-HIV analogues: a small chemical substitution allows relevant activities

Cited by 8 publications

References 59 publications

Azvudine, A Novel Nucleoside Reverse Transcriptase Inhibitor Showed Good Drug Combination Features and Better Inhibition on Drug-Resistant Strains than Lamivudine In Vitro

Azvudine, A Novel Nucleoside Reverse Transcriptase Inhibitor Showed Good Drug Combination Features and Better Inhibition on Drug-Resistant Strains than Lamivudine In Vitro

Comparative Efficacy of Lamivudine and Emtricitabine: A Systematic Review and Meta-Analysis of Randomized Trials

Multidrug resistance-associated ABC transporters – too much of one thing, good for nothing

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