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1.
Pharmacol Res Perspect ; 8(6): e00674, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33124786

RESUMO

SARS-CoV-2, a member of the coronavirus family, has caused a global public health emergency. Based on our analysis of hepatitis C virus and coronavirus replication, and the molecular structures and activities of viral inhibitors, we previously reasoned that the FDA-approved hepatitis C drug EPCLUSA (Sofosbuvir/Velpatasvir) should inhibit coronaviruses, including SARS-CoV-2. Here, using model polymerase extension experiments, we demonstrate that the active triphosphate form of Sofosbuvir is incorporated by low-fidelity polymerases and SARS-CoV RNA-dependent RNA polymerase (RdRp), and blocks further incorporation by these polymerases; the active triphosphate form of Sofosbuvir is not incorporated by a host-like high-fidelity DNA polymerase. Using the same molecular insight, we selected 3'-fluoro-3'-deoxythymidine triphosphate and 3'-azido-3'-deoxythymidine triphosphate, which are the active forms of two other anti-viral agents, Alovudine and AZT (an FDA-approved HIV/AIDS drug) for evaluation as inhibitors of SARS-CoV RdRp. We demonstrate the ability of two of these HIV reverse transcriptase inhibitors to be incorporated by SARS-CoV RdRp where they also terminate further polymerase extension. Given the 98% amino acid similarity of the SARS-CoV and SARS-CoV-2 RdRps, we expect these nucleotide analogues would also inhibit the SARS-CoV-2 polymerase. These results offer guidance to further modify these nucleotide analogues to generate more potent broad-spectrum anti-coronavirus agents.


Assuntos
Antivirais/farmacologia , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , /antagonistas & inibidores , Betacoronavirus/enzimologia , Carbamatos/farmacologia , Infecções por Coronavirus/virologia , Didesoxinucleotídeos/farmacologia , Combinação de Medicamentos , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Humanos , Pandemias , Pneumonia Viral/virologia , Sofosbuvir/farmacologia , Nucleotídeos de Timina/farmacologia , Zidovudina/análogos & derivados , Zidovudina/farmacologia
2.
Cell Metab ; 29(4): 871-885.e5, 2019 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-30853213

RESUMO

Mice deficient for SIRT6 exhibit a severely shortened lifespan, growth retardation, and highly elevated LINE1 (L1) activity. Here we report that SIRT6-deficient cells and tissues accumulate abundant cytoplasmic L1 cDNA, which triggers strong type I interferon response via activation of cGAS. Remarkably, nucleoside reverse-transcriptase inhibitors (NRTIs), which inhibit L1 retrotransposition, significantly improved health and lifespan of SIRT6 knockout mice and completely rescued type I interferon response. In tissue culture, inhibition of L1 with siRNA or NRTIs abrogated type I interferon response, in addition to a significant reduction of DNA damage markers. These results indicate that L1 activation contributes to the pathologies of SIRT6 knockout mice. Similarly, L1 transcription, cytoplasmic cDNA copy number, and type I interferons were elevated in the wild-type aged mice. As sterile inflammation is a hallmark of aging, we propose that modulating L1 activity may be an important strategy for attenuating age-related pathologies.


Assuntos
Inflamação/metabolismo , Proteínas de Ligação a RNA/metabolismo , Sirtuínas/metabolismo , Fatores Etários , Animais , Didesoxinucleotídeos/administração & dosagem , Didesoxinucleotídeos/farmacologia , Feminino , Masculino , Camundongos , Camundongos Endogâmicos , Camundongos Knockout , Proteínas de Ligação a RNA/antagonistas & inibidores , Sirtuínas/deficiência , Estavudina/administração & dosagem , Estavudina/farmacologia , Nucleotídeos de Timina/administração & dosagem , Nucleotídeos de Timina/farmacologia , Zidovudina/administração & dosagem , Zidovudina/análogos & derivados , Zidovudina/farmacologia
3.
Vopr Virusol ; 63(5): 212-217, 2018.
Artigo em Russo | MEDLINE | ID: mdl-30550097

RESUMO

OBJECTIVES: The goal of this work was to study the immunological and virological efficacy of the domestic antiretroviral drug nicavir (at the optimal dose, as proven by previous clinical studies) with lamivudine, in comparison with other drugs of the group of nucleoside reverse transcriptase inhibitors in combination with kaletra in perinatal HIV chemoprophylaxis regimens. METHODS: 658 pregnant women aged 16-39 years and children born to them were examined. The first group (281 people) and the third group (66 people) received the nicavir (manufactured by AZT PHARMA KB LLC) with lamivudine in combination with calyx; the second (281 people) and the fourth (30 people) of the comparison group, stag and zidovudine, respectively, with lamivudine in combination with calyx. The effectiveness of CP was assessed from the increase in the number of CD4 lymphocytes, reduction of the viral load, and the number of children born without HIV DNA in the blood. RESULTS: Against the backdrop of the therapy, the viral load below the detectable level and the positive dynamics of CD4 lymphocytes were registered in all examined women prior to childbirth. When applying the scheme of niacavir + lamivudine + kaletra, a more rapid decrease in the level of BH, most pronounced by week 4 of therapy, was found, as compared with the rate of decline of the same index in pregnant comparison groups. CONCLUSIONS: The obtained results allow us to consider ART with the inclusion of nicavir effective and recommend its priority use in perinatal prevention of mother-to-child transmission of HIV.


Assuntos
Fármacos Anti-HIV/administração & dosagem , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Organofosfonatos/administração & dosagem , Zidovudina/análogos & derivados , Adolescente , Adulto , Linfócitos T CD4-Positivos/efeitos dos fármacos , Quimioprevenção/métodos , Combinação de Medicamentos , Feminino , Infecções por HIV/patologia , Infecções por HIV/transmissão , Infecções por HIV/virologia , HIV-1/patogenicidade , Humanos , Lactente , Recém-Nascido , Transmissão Vertical de Doença Infecciosa , Lamivudina/administração & dosagem , Lopinavir/administração & dosagem , Assistência Perinatal , Ritonavir/administração & dosagem , Carga Viral/efeitos dos fármacos , Adulto Jovem , Zidovudina/administração & dosagem
4.
Chem Biol Interact ; 294: 135-143, 2018 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-30120923

RESUMO

The present study evaluated the neuroprotective effects of one selenium-containing AZT derivative compound (S1073) in memory and learning impairment caused by Intracerebroventricular-streptozotocin (ICV-STZ). ICV-STZ in mice causes impairment of energy metabolism with oxidative damage and cholinergic dysfunction, and provides a relevant model for sporadic dementia of Alzheimer's type (AD). Acetylcolinesterase (AChE), Catalase (CAT), dichlorofluorescein oxidation (DCFH), TBARS and thiol content were measured. Swiss adult mice were pre-treated with S1073 [1 mmol/kg] (i.p.) and after 30 min of the injection received a bilateral dose of STZ [11.3 µmol/l]. After 8 days' STZ injection, we performed the behavioral experiments (Beaker test, Open field and Morris water maze task). ICV-STZ caused significant learning and memory impairments, which were significantly improved by S1073 pre-treatment. A significant increase in cerebral DFCH, TBARS levels and AChE activity and a disturbance in the memory and learning were observed in ICV-STZ injected animals. S1073 significantly ameliorated all alterations induced by ICV-STZ in mice. All these findings support the neuroprotective role of S1073 in mice model of Alzheimer's dementia-type induced by ICV-STZ, which may be associated with its antioxidant activity and/or with its inhibitory effect in brain AChE. In fact, in silico analysis indicated that S1073 may be an inhibitor of AChE.


Assuntos
Comportamento Animal/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Compostos Organosselênicos/farmacologia , Zidovudina/análogos & derivados , Zidovudina/farmacologia , Acetilcolinesterase/química , Acetilcolinesterase/metabolismo , Doença de Alzheimer/induzido quimicamente , Doença de Alzheimer/prevenção & controle , Animais , Sítios de Ligação , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Catalase/metabolismo , Domínio Catalítico , Modelos Animais de Doenças , Infusões Intraventriculares , Aprendizagem em Labirinto/efeitos dos fármacos , Memória/efeitos dos fármacos , Camundongos , Simulação de Acoplamento Molecular , Fármacos Neuroprotetores/metabolismo , Fármacos Neuroprotetores/uso terapêutico , Compostos Organosselênicos/metabolismo , Compostos Organosselênicos/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos , Estreptozocina , Zidovudina/metabolismo , Zidovudina/uso terapêutico
5.
Anal Bioanal Chem ; 410(21): 5245-5253, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29947896

RESUMO

Asymmetric flow field-flow fractionation (AF4) coupled with UV-Vis spectroscopy, multi-angle light scattering (MALS) and refractive index (RI) detection has been applied for the characterization of MIL-100(Fe) nanoMOFs (metal-organic frameworks) loaded with nucleoside reverse transcriptase inhibitor (NRTI) drugs for the first time. Empty nanoMOFs and nanoMOFs loaded with azidothymidine derivatives with three different degrees of phosphorylation were examined: azidothymidine (AZT, native drug), azidothymidine monophosphate (AZT-MP), and azidothymidine triphosphate (AZT-TP). The particle size distribution and the stability of the nanoparticles when interacting with drugs have been determined in a time frame of 24 h. Main achievements include detection of aggregate formation in an early stage and monitoring nanoMOF morphological changes as indicators of their interaction with guest molecules. AF4-MALS proved to be a useful methodology to analyze nanoparticles engineered for drug delivery applications and gave fundamental data on their size distribution and stability. Graphical abstract ᅟ.


Assuntos
Fármacos Anti-HIV/administração & dosagem , Complexos de Coordenação/química , Portadores de Fármacos/química , Estruturas Metalorgânicas/química , Nanopartículas/química , Zidovudina/administração & dosagem , Fármacos Anti-HIV/química , Antimetabólitos/administração & dosagem , Antimetabólitos/química , Didesoxinucleotídeos/administração & dosagem , Didesoxinucleotídeos/química , Difusão Dinâmica da Luz , Fracionamento por Campo e Fluxo , Modelos Moleculares , Tamanho da Partícula , Refratometria , Espectrofotometria Ultravioleta , Nucleotídeos de Timina/administração & dosagem , Nucleotídeos de Timina/química , Zidovudina/análogos & derivados , Zidovudina/química
6.
Chembiochem ; 19(18): 1939-1943, 2018 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-29953711

RESUMO

Metabolic incorporation of bioorthogonal functional groups into cellular nucleic acids can be impeded by insufficient phosphorylation of nucleosides. Previous studies found that 5azidomethyl-2'-deoxyuridine (AmdU) was incorporated into the DNA of HeLa cells expressing a low-fidelity thymidine kinase, but not by wild-type HeLa cells. Here we report that membrane-permeable phosphotriester derivatives of AmdU can exhibit enhanced incorporation into the DNA of wild-type cells and animals. AmdU monophosphate derivatives bearing either 5'-bispivaloyloxymethyl (POM), 5'-bis-(4-acetoxybenzyl) (AB), or "Protide" protective groups were used to mask the phosphate group of AmdU prior to its entry into cells. The POM derivative "POM-AmdU" exhibited better chemical stability, greater metabolic incorporation efficiency, and lower toxicity than "AB-AmdU". Remarkably, the addition of POM-AmdU to the water of zebrafish larvae enabled the biosynthesis of azide-modified DNA throughout the body.


Assuntos
Azidas/química , DNA/química , Nucleotídeos/química , Zidovudina/análogos & derivados , Animais , Azidas/metabolismo , Permeabilidade da Membrana Celular , Química Click , DNA/metabolismo , Ésteres/química , Ésteres/metabolismo , Células HeLa , Humanos , Nucleotídeos/metabolismo , Peixe-Zebra , Zidovudina/química , Zidovudina/metabolismo
7.
AIDS Res Hum Retroviruses ; 34(2): 228-233, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29084434

RESUMO

Historically, in HIV patients, the K65R mutation and thymidine analogue mutations (TAMs) have been reported to rarely coexist. We retrospectively reviewed genotype data from paired samples in a cohort of HIV-1-infected Nigerian patients failing first-line antiretroviral therapies containing zidovudine (AZT) or tenofovir (TDF). Samples for each patient were taken at initial confirmed virological failure ≥1000 copies/ml (S1) and then at the latest available sample with viral load ≥1000 copies/ml before switch to second line (S2). Among 103 patients failing AZT, 19 (18.4%) had TAM-1s, 29 (28.2%) TAM-2s, and 21 (20.4%) mixed TAMs by S2. In contrast, in the 87 patients failing TDF, drug resistance mutations at S2 included K65R in 56 (64.4%), TAM-1s in 1 (1.1%), and TAM-2s in 25 patients (28.7%). Interestingly, 30.4% of patients with K65R in our study developed TAMs. These were exclusively K219E ± D67N and were not predicted to confer a resistance cost to future AZT-containing regimens.


Assuntos
Infecções por HIV/tratamento farmacológico , HIV-1/genética , Inibidores da Transcriptase Reversa/farmacologia , Tenofovir/farmacologia , Carga Viral/efeitos dos fármacos , Zidovudina/farmacologia , Farmacorresistência Viral/genética , Infecções por HIV/genética , Transcriptase Reversa do HIV/antagonistas & inibidores , Transcriptase Reversa do HIV/genética , HIV-1/efeitos dos fármacos , Humanos , Nigéria , Estudos Retrospectivos , Falha de Tratamento , Zidovudina/análogos & derivados
8.
Toxicol Sci ; 160(1): 30-46, 2017 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-29036705

RESUMO

Considering a novel series of zidovudine (AZT) derivatives encompassing selenoaryl moieties promising candidates as therapeutics, we examined the toxicities elicited by AZT and derivatives 5'-(4-Chlorophenylseleno)zidovudine (SZ1); 5'-(Phenylseleno)zidovudine (SZ2); and 5'-(4-Methylphenylseleno)zidovudine (SZ3) in healthy cells and in mice. Resting and stimulated cultured human peripheral blood mononuclear cells (PBMCs) were treated with the compounds at concentrations ranging from 10 to 200 µM for 24 and/or 72 h. Adult mice received a single injection of compounds (100 µmol/kg, s.c.) and 72 h after administration, hepatic/renal biomarkers were analyzed. Resting and stimulated PBMCs exposed to SZ1 displayed loss of viability, increased reactive species production, disruption in cell cycle, apoptosis and increased transcript levels and production of pro-inflammatory cytokines. In a mild way, most of these effects were also induced by SZ2. AZT and SZ3 did not cause significant toxicity towards resting PBMCs. Differently, both compounds elicited apoptosis and S phase arrest in stimulated cells. AZT and derivatives administration did not change the body weight and plasma biochemical markers in mice. However, the absolute weight and organ-to-body weight ratio of liver, kidneys and spleen were altered in AZT, SZ1-, and SZ2-treated mice. Our results highlighted the involvement of derivatives SZ1 and SZ2 in redox and immunological dyshomeostasis leading to activation of apoptotic signaling pathways in healthy cells under different division phases. On the other hand, the derivative SZ3 emerged as a promising candidate for further viral infection/antitumor studies as a new effective therapy with low toxicity for immune cells and after acute in vivo treatment.


Assuntos
Antineoplásicos/toxicidade , Calcogênios/toxicidade , Leucócitos Mononucleares/efeitos dos fármacos , Zidovudina/toxicidade , Animais , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Comportamento Animal/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Citocinas/genética , Citocinas/metabolismo , Relação Dose-Resposta a Droga , Regulação da Expressão Gênica , Humanos , Mediadores da Inflamação/metabolismo , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Leucócitos Mononucleares/metabolismo , Leucócitos Mononucleares/patologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos , Tamanho do Órgão/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Medição de Risco , Pontos de Checagem da Fase S do Ciclo Celular/efeitos dos fármacos , Zidovudina/análogos & derivados
9.
Bioorg Med Chem ; 25(19): 5128-5132, 2017 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-28712845

RESUMO

The brain provides a sanctuary site for HIV due, in part, to poor penetration of antiretroviral agents at the blood-brain barrier. This lack of penetration is partially attributed to drug efflux transporters such as P-glycoprotein (P-gp) and ABCG2. Inhibition of both ABCG2 and P-gp is critical for enhancing drug accumulation into the brain. In this work, we have developed a class of homodimers based on the HIV reverse transcriptase inhibitor azidothymidine (AZT) that effectively inhibits P-gp and ABCG2. These agents block transporter mediated efflux of the P-gp substrate calcein-AM and the ABCG2 substrate mitoxantrone. The homodimers function by interacting with the transporter drug binding sites as demonstrated by competition studies with the photo-affinity agent and P-gp/ABCG2 substrate [125I]iodoarylazidoprazosin. As such, these dual inhibitors of both efflux transporters provide a model for the future development of delivery vehicles for antiretroviral agents to the brain.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Transporte Biológico/efeitos dos fármacos , Barreira Hematoencefálica/efeitos dos fármacos , Proteínas de Neoplasias/antagonistas & inibidores , Zidovudina/análogos & derivados , Zidovudina/farmacologia , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Antivirais/química , Antivirais/farmacologia , Barreira Hematoencefálica/metabolismo , Linhagem Celular , Dimerização , Humanos , Proteínas de Neoplasias/metabolismo
10.
Bioorg Med Chem Lett ; 27(8): 1627-1632, 2017 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-28285913

RESUMO

The development of prodrugs has progressed with the aim of improving drug bioavailability by overcoming various barriers that reduce drug benefits in clinical use, such as stability, duration, water solubility, side effect profile, and taste. Many conventional drugs act as the precursors of an active agent in vivo; for example, the anti-HIV agent azidothymidine (AZT) is converted into its corresponding active triphosphate ester in the body, meaning that AZT is a prodrug in the broadest sense. However prodrug design is generally difficult owing to the lack of general versatility. Thus, these prodrugs, broadly defined, are often discovered by chance or trial-and-error. Recently, many prodrugs that could release the corresponding parent drugs with or without enzymatic action under physiological conditions have been reported. These prodrugs can be easily designed and synthesized because of their generally applicable modifications. This digest paper provides an overview of recent development in prodrug strategies for drugs with a carboxylic acid or hydroxyl/amino group on the basis of a generally applicable modification strategy, such as esterification, amidation, or benzylation.


Assuntos
Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacocinética , Desenho de Fármacos , Pró-Fármacos/química , Pró-Fármacos/farmacocinética , Amidas/química , Amidas/metabolismo , Amidas/farmacocinética , Animais , Fármacos Anti-HIV/metabolismo , Compostos de Benzil/química , Compostos de Benzil/metabolismo , Compostos de Benzil/farmacocinética , Disponibilidade Biológica , Ácidos Carboxílicos/química , Ácidos Carboxílicos/metabolismo , Ácidos Carboxílicos/farmacocinética , Esterificação , HIV/efeitos dos fármacos , Infecções por HIV/tratamento farmacológico , Humanos , Pró-Fármacos/metabolismo , Solubilidade , Zidovudina/análogos & derivados , Zidovudina/metabolismo , Zidovudina/farmacocinética
11.
Hum Exp Toxicol ; 36(9): 910-918, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27777322

RESUMO

Acquired immunodeficiency syndrome (AIDS) is a worldwide disease characterized by impairments of immune function. AIDS can be associated with oxidative stress (OS) that can be linked to selenium (Se) deficiency. Se is fundamental for the synthesis of selenoproteins, such as glutathione peroxidase and thioredoxin reductase. These enzymes catalyze the decomposition of reactive oxygen species and contribute to maintain equilibrium in cell redox status. Literature data indicate that organoselenium compounds, such as ebselen and diphenyl diselenide, have antioxidant properties in vitro and in vivo models associated with OS. Nevertheless, selenocompounds can also react and oxidize thiols groups, inducing toxicity in mammals. Here, we tested the potential cytotoxic and genotoxic properties of six analogs of the prototypal anti-HIV drug azidothymidine (AZT) containing Se (5'-Se-(phenyl)zidovudine; 5'-Se-(1,3,5-trimethylphenyl)zidovudine; 5'-Se-(1-naphtyl)zidovudine; 5'-Se-(4-chlorophenyl)zidovudine) (C4); 5'-Se-(4-methylphenyl)zidovudine (C5); and 5'-(4-methylbenzoselenoate)zidovudine). C5 increased the rate of dithiothreitol oxidation (thiol oxidase activity) and C2-C4 and C6 (at 100 µM) increased DNA damage index (DI) in human leukocytes. Moreover, C5 (200 µM) decreased human leukocyte viability to about 50%. Taken together, these results indicated the low in vitro toxicity in human leukocytes of some Se-containing analogs of AZT.


Assuntos
Fármacos Anti-HIV/toxicidade , Leucócitos/efeitos dos fármacos , Compostos Organosselênicos/toxicidade , Zidovudina/análogos & derivados , Zidovudina/toxicidade , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Ensaio Cometa , Dano ao DNA , Humanos
12.
Biochemistry ; 56(1): 33-46, 2017 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-27936595

RESUMO

Reverse transcriptases (RTs) are typically assayed in vitro with 5-10 mM Mg2+, whereas the free Mg2+ concentration in cells is much lower. Artificially high Mg2+ concentrations used in vitro can misrepresent different properties of human immunodeficiency virus (HIV) RT, including fidelity, catalysis, pausing, and RNase H activity. Here, we analyzed nucleoside (NRTIs) and non-nucleoside RT inhibitors (NNRTIs) in primer extension assays at different concentrations of free Mg2+. At low concentrations of Mg2+, NRTIs and dideoxynucleotides (AZTTP, ddCTP, ddGTP, and 3TCTP) inhibited HIV-1 and HIV-2 RT synthesis less efficiently than they did with large amounts of Mg2+, whereas inhibition by the "translocation-defective RT inhibitor" EFdA (4'-ethynyl-2-fluoro-2'-deoxyadenosine) was unaffected by Mg2+ concentrations. Steady-state kinetic analyses revealed that the reduced level of inhibition at low Mg2+ concentrations resulted from a 3-9-fold (depending on the particular nucleotide and inhibitor) less efficient incorporation (based on kcat/Km) of these NRTIs under this condition compared to incorporation of natural dNTPs. In contrast, EFdATP was incorporated with an efficiency similar to that of its analogue dATP at low Mg2+ concentrations. Unlike NRTIs, NNRTIs (nevirapine, efavirenz, and rilviripine), were approximately 4-fold (based on IC50 values) more effective at low than at high Mg2+ concentrations. Drug-resistant HIV-1 RT mutants also displayed the Mg2+-dependent difference in susceptibility to NRTIs and NNRTIs. In summary, analyzing the efficiency of inhibitors under more physiologically relevant low-Mg2+ conditions yielded results dramatically different from those from measurements using commonly employed high-Mg2+ in vitro conditions. These results also emphasize differences in Mg2+ sensitivity between the translocation inhibitor EFdATP and other NRTIs.


Assuntos
Didesoxinucleotídeos/farmacologia , Transcriptase Reversa do HIV/antagonistas & inibidores , Magnésio/farmacologia , Nucleosídeos/farmacologia , Inibidores da Transcriptase Reversa/farmacologia , Nucleotídeos de Desoxicitosina/farmacologia , Nucleotídeos de Desoxiguanina/farmacologia , Relação Dose-Resposta a Droga , Interações Medicamentosas , Eletroforese em Gel de Poliacrilamida , Transcriptase Reversa do HIV/genética , Transcriptase Reversa do HIV/metabolismo , Humanos , Cinética , Mutação , Nucleotídeos de Timina/farmacologia , Zalcitabina/farmacologia , Zidovudina/análogos & derivados , Zidovudina/farmacologia
13.
AIDS ; 31(4): 501-509, 2017 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-27941394

RESUMO

OBJECTIVE: Use of zidovudine (ZDV) in antiretroviral therapy is limited by toxicity and twice daily (b.i.d.) dosing. Fozivudine (FZD) is a ZDV prodrug, which is activated intracellularly to ZDV-monophosphate especially in mononuclear cells but not in bone marrow cells. FZD promises improved myelotoxicity and once daily (o.d.) dosing. DESIGN: Randomized clinical trial. METHODS: We conducted an open-label, phase II, proof-of-concept trial investigating three different FZD doses (800 mg o.d., 600 mg b.i.d., 1200 mg o.d.) versus ZDV (300 mg b.i.d.) in combination with lamivudine and efavirenz in HIV-infected, ART-naive patients from Tanzania and Côte d'Ivoire. The primary objective was to demonstrate virological efficacy after 24 weeks in intent-to treat and per-protocol analysis. Secondary endpoints included safety and pharmacokinetic outcomes. RESULTS: Of 119 participants included in the intent-to treat analysis, HIV RNA less than 50 copies/ml at 24 weeks was observed in 64 of 88 (73%) patients in the combined FZD arms versus 24 of 31 (77%) in the ZDV arm (RR 0.94, 95% confidence interval 0.75-1.18). In the per-protocol analysis, responses were 64 of 77 (87%) versus 23 of 29 (79%), respectively (RR 1.09, 95% confidence interval 0.89-1.34). Outcomes were similar between FZD arms. Overall, treatments were well tolerated. Severe or worse anaemia occurred in two cases (one related to FZD, one to ZDV), grade III/IV neutropenia was less frequent in FZD compared with ZDV arms (22 versus 42%, P = 0.035). Pharmacokinetic analysis supported o.d. administration of FZD. CONCLUSION: Virological 24-week efficacy was demonstrated in b.i.d. and o.d. administered FZD-based regimens. Reduced myelotoxicity of FZD needs to be confirmed in a larger trial.


Assuntos
Antirretrovirais/administração & dosagem , Terapia Antirretroviral de Alta Atividade/métodos , Infecções por HIV/tratamento farmacológico , Lipídeos/administração & dosagem , Zidovudina/análogos & derivados , Adulto , Antirretrovirais/efeitos adversos , Antirretrovirais/farmacocinética , Terapia Antirretroviral de Alta Atividade/efeitos adversos , Costa do Marfim , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Feminino , Humanos , Lipídeos/efeitos adversos , Lipídeos/farmacocinética , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Resposta Viral Sustentada , Tanzânia , Resultado do Tratamento , Zidovudina/administração & dosagem , Zidovudina/efeitos adversos , Zidovudina/farmacocinética
14.
Vopr Virusol ; 62(1): 5-11, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29323840

RESUMO

Federation Convincing evidence for high therapeutic activity and tolerability of Phosphazide in the treatment of HIV/AIDS-infection is given. Phosphazide is currently used in various regimens of highly active antiretroviral therapy, as well as in the HIV therapy in patients with simultaneously acquired chronic hepatitis C or tuberculosis. Therapeutic possibilities of Phosphazide were clearly manifested in the prevention of HIV transmission from mother to child. There is every reason to use Phosphazide in first-line antiretroviral therapy.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , HIV/efeitos dos fármacos , Transmissão Vertical de Doença Infecciosa/prevenção & controle , Organofosfonatos/uso terapêutico , Complicações Infecciosas na Gravidez/tratamento farmacológico , Zidovudina/análogos & derivados , Fármacos Anti-HIV/farmacocinética , Terapia Antirretroviral de Alta Atividade/métodos , Feminino , Feto , HIV/genética , HIV/metabolismo , Infecções por HIV/transmissão , Infecções por HIV/virologia , Humanos , Organofosfonatos/farmacocinética , Gravidez , Complicações Infecciosas na Gravidez/virologia , Resultado do Tratamento , Zidovudina/farmacocinética , Zidovudina/uso terapêutico
15.
Colloids Surf B Biointerfaces ; 148: 385-391, 2016 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-27636322

RESUMO

Anti-HIV prodrugs are recently focused on due to their ability of self-assembly, macrophage targeting, and enhanced antiviral effects. Here, an amphiphilic prodrug of zidovudine, an anti-HIV nucleoside analogue, 5'-cholesteryl-ethyl-phosphoryl zidovudine (CEPZ) was synthesized. CEPZ showed some unique physicochemical properties. The solubility of CEPZ in the noncompetitive solvents chloroform and tetrahydrofuran (THF) was very high based on the hydrogen bonds between zidovudine groups, though CEPZ was sparing soluble in alcohols and almost insoluble in water. The typical amphiphilic property of CEPZ was demonstrated according to the Langmuir monolayers at the air/water interface. The LogP of CEPZ was high to 13.78, indicating the high hydrophobicity of amphiphilic CEPZ similar to phospholipids. Homogenous and stable self-assemblies were formed with the mean size of 128.7nm and the zeta potential of -35.4mV after injecting the CEPZ-in-THF solution into water. Hydrophobic interaction between the cholesteryl moieties of CEPZ could drive molecular self-assembly and lead to the formation of spherical vesicles. CEPZ self-assemblies showed strong stability even under high temperature and gravity probably due to the high surface charge. CEPZ was very slowly degraded in neutral solutions (e.g., pH 7.4), but fast in acid solutions (e.g., pH 5.0) and some tissue homogenates. CEPZ was quickly eliminated from the circulation and distributed into the mononuclear phagocyte system (MPS) including the liver, spleen and lung after bolus intravenous administration of CEPZ self-assemblies to mice. The MPS targeting effect of CEPZ self-assemblies makes them become a promising self-assembled drug delivery system to eradicate the HIV hidden in the macrophages.


Assuntos
Fármacos Anti-HIV/química , Ésteres do Colesterol/química , Pró-Fármacos/química , Zidovudina/análogos & derivados , Zidovudina/química , Animais , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/farmacocinética , Linhagem Celular , Ésteres do Colesterol/síntese química , Ésteres do Colesterol/farmacocinética , Concentração de Íons de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Macaca mulatta , Macrófagos/metabolismo , Masculino , Camundongos , Microscopia Eletrônica de Transmissão , Modelos Químicos , Estrutura Molecular , Pró-Fármacos/síntese química , Pró-Fármacos/farmacocinética , Ratos Sprague-Dawley , Solubilidade , Solventes/química , Distribuição Tecidual , Zidovudina/síntese química , Zidovudina/farmacocinética
16.
Vopr Virusol ; 61(1): 34-9, 2016.
Artigo em Russo | MEDLINE | ID: mdl-27145599

RESUMO

Efficacy, safety, and economical aspects of treatment with abacavir, zidovudine, stavudine, and phosphazide in the schemes of antiretroviral therapy of the HIV-infected patients receiving therapy for hepatitis C virus were tested. Clinical, immunological, and virologic efficacy of treatment and dynamics of hemoglobin, thrombocytes, and alanine aminotransferase as markers of common adverse events recorded at the start of the antiviral therapy of chronic hepatitis C and after 4, 8, 12, 24, 48 weeks of the treatment were evaluated. The usage of these drugs in the schemes of antiretroviral therapy exhibited efficacy, high tolerability and safety for all HIV reverse transcriptase inhibitors.


Assuntos
Didesoxinucleosídeos/uso terapêutico , Infecções por HIV/tratamento farmacológico , Hepatite C Crônica/tratamento farmacológico , Organofosfonatos/uso terapêutico , Inibidores da Transcriptase Reversa/uso terapêutico , Estavudina/uso terapêutico , Zidovudina/análogos & derivados , Zidovudina/uso terapêutico , Adulto , Alanina Transaminase/sangue , Biomarcadores/sangue , Plaquetas/efeitos dos fármacos , Linfócitos T CD4-Positivos/efeitos dos fármacos , Contagem de Células , Coinfecção , Didesoxinucleosídeos/economia , Feminino , Genótipo , Infecções por HIV/sangue , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , HIV-1/genética , HIV-1/crescimento & desenvolvimento , Hemoglobinas/metabolismo , Hepacivirus/efeitos dos fármacos , Hepacivirus/genética , Hepacivirus/crescimento & desenvolvimento , Hepatite C Crônica/sangue , Hepatite C Crônica/virologia , Humanos , Masculino , Organofosfonatos/economia , Inibidores da Transcriptase Reversa/economia , Estavudina/economia , Zidovudina/economia
17.
Nucleic Acids Res ; 44(5): 2310-22, 2016 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-26850643

RESUMO

We analyzed a multi-drug resistant (MR) HIV-1 reverse transcriptase (RT), subcloned from a patient-derived subtype CRF02_AG, harboring 45 amino acid exchanges, amongst them four thymidine analog mutations (TAMs) relevant for high-level AZT (azidothymidine) resistance by AZTMP excision (M41L, D67N, T215Y, K219E) as well as four substitutions of the AZTTP discrimination pathway (A62V, V75I, F116Y and Q151M). In addition, K65R, known to antagonize AZTMP excision in HIV-1 subtype B was present. Although MR-RT harbored the most significant amino acid exchanges T215Y and Q151M of each pathway, it exclusively used AZTTP discrimination, indicating that the two mechanisms are mutually exclusive and that the Q151M pathway is obviously preferred since it confers resistance to most nucleoside inhibitors. A derivative was created, additionally harboring the TAM K70R and the reversions M151Q as well as R65K since K65R antagonizes excision. MR-R65K-K70R-M151Q was competent of AZTMP excision, whereas other combinations thereof with only one or two exchanges still promoted discrimination. To tackle the multi-drug resistance problem, we tested if the MR-RTs could still be inhibited by RNase H inhibitors. All MR-RTs exhibited similar sensitivity toward RNase H inhibitors belonging to different inhibitor classes, indicating the importance of developing RNase H inhibitors further as anti-HIV drugs.


Assuntos
Farmacorresistência Viral Múltipla/genética , Inibidores Enzimáticos/farmacologia , Transcriptase Reversa do HIV/antagonistas & inibidores , HIV-1/efeitos dos fármacos , Ribonuclease H do Vírus da Imunodeficiência Humana/antagonistas & inibidores , Sequência de Aminoácidos , Substituição de Aminoácidos , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Clonagem Molecular , Didesoxinucleotídeos/química , Didesoxinucleotídeos/farmacologia , Inibidores Enzimáticos/química , Escherichia coli/genética , Escherichia coli/metabolismo , Expressão Gênica , Genótipo , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Transcriptase Reversa do HIV/genética , Transcriptase Reversa do HIV/metabolismo , HIV-1/enzimologia , HIV-1/genética , HIV-1/isolamento & purificação , Humanos , Dados de Sequência Molecular , Mutagênese Sítio-Dirigida , Mutação , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Ribonuclease H do Vírus da Imunodeficiência Humana/genética , Ribonuclease H do Vírus da Imunodeficiência Humana/metabolismo , Nucleotídeos de Timina/química , Nucleotídeos de Timina/farmacologia , Zidovudina/análogos & derivados , Zidovudina/química , Zidovudina/farmacologia
18.
J Acquir Immune Defic Syndr ; 72(3): 246-53, 2016 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-26859826

RESUMO

OBJECTIVES: Zidovudine (AZT) is mainly used to prevent mother-to-child HIV-1 transmission (PMTCT). Despite serious concerns on AZT-associated toxicity, there is little information on pharmacokinetics of intracellular AZT metabolites in infants. METHODS: We conducted a prospective study in 31 HIV-uninfected infants who received AZT for PMTCT. Blood samples were obtained from 14 infants on postdelivery days (PDD) 1, 7, 14, and 28 and from 17 infants at 0 and 4 hours after dosing on PDD-1. Plasma AZT concentrations (pAZT) and intracellular concentrations of AZT-monophosphate (icAZT-MP), diphosphate (icAZT-DP), and triphosphate (icAZT-TP) were determined. RESULTS: Plasma AZT and icAZT-MP concentrations were 2713 nmol/L and 79 fmol/10 cells in PDD-1, but decreased to 1437 nmol/L and 31 fmol/10 cells by PDD-28 (P = 0.02 and P = 0.07 for all PDDs, respectively), whereas those of icAZT-DP and icAZT-TP remained low throughout the sampling period (P = 0.29 and P = 0.61 for all PDDs, respectively) There were no differences in icAZT-TP between infants of the 2 mg/kg 4 times a day dose and 4 mg/kg twice daily dose (P = 0.25), whereas pAZT and icAZT-MP levels were higher in the latter (P < 0.01 and <0.01, respectively). The pAZT and icAZT-MP significantly increased from 0 to 4 hours after dosing (P < 0.001 and <0.001, respectively), whereas icAZT-DP, icAZT-TP levels were not changed (P = 0.41 and 0.33, respectively). CONCLUSIONS: The level of icAZT-TP did not change with age, time, or a single dose despite the wide range of pAZT concentration. A safer dosage needs to be determined because high pAZT levels do not parallel those of icAZT-TP.


Assuntos
Fármacos Anti-HIV/farmacocinética , Didesoxinucleotídeos/farmacocinética , Infecções por HIV/prevenção & controle , Infecções por HIV/transmissão , HIV-1/efeitos dos fármacos , Transmissão Vertical de Doença Infecciosa/prevenção & controle , Complicações Infecciosas na Gravidez/tratamento farmacológico , Nucleotídeos de Timina/farmacocinética , Zidovudina/análogos & derivados , Zidovudina/farmacocinética , Adulto , Fármacos Anti-HIV/sangue , Cromatografia Líquida de Alta Pressão/métodos , Didesoxinucleotídeos/sangue , Feminino , Infecções por HIV/tratamento farmacológico , Humanos , Recém-Nascido , Estudos Longitudinais , Masculino , Mães , Gravidez , Complicações Infecciosas na Gravidez/imunologia , Estudos Prospectivos , Nucleotídeos de Timina/sangue , Resultado do Tratamento , Adulto Jovem , Zidovudina/sangue
19.
Klin Med (Mosk) ; 94(4): 295-299, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-28957610

RESUMO

AIM: Comparative assessment of the efficiency of application of different therapeutic schemes for post-contact prevention (PCP) of HIV infection in health providers. METHODS: Medical personnel that had professional contacts with HIV-infected patients (n=44) were given medications for PCP. 19 of them (group 1) used phosphazide, 25 (group 2) combivir (lamivudine + zidovudine) in combination with kaletra for 4 weeks after the contact. Phosphazide (AZT Farma K.B., Russia) was used at a dose of 0.4 g twice daily, other medications in standard doses. The results were evaluated 4 weeks, 3, 6, and 12 months after PCP from the safety of the treatment and the absence of professional HIV infection. RESULTS: The medical personnel showed no signs of HIV infection throughout the entire period of observation. The safety of therapy was confirmed by the absence of myelohepatotoxic effect of the preparations. Combivir therapy caused a 1.8-fold rise in AST activity of within 4 weeks after onset of PCP (p<0,05). Phosphazide produced no such effect. CONCLUSION: The above results indicate that both schemes ofantiretroviral activity are 100% efficient as PCP of HIV infection, but phosphazide has an advantage of higher safety and better tolerability.


Assuntos
Infecções por HIV , Transmissão de Doença Infecciosa do Paciente para o Profissional/prevenção & controle , Lamivudina/administração & dosagem , Lopinavir/administração & dosagem , Organofosfonatos/administração & dosagem , Profilaxia Pós-Exposição/métodos , Ritonavir/administração & dosagem , Zidovudina/análogos & derivados , Adulto , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/efeitos adversos , Combinação de Medicamentos , Monitoramento de Medicamentos/métodos , Feminino , Infecções por HIV/prevenção & controle , Infecções por HIV/transmissão , Humanos , Lopinavir/efeitos adversos , Masculino , Organofosfonatos/efeitos adversos , Ritonavir/efeitos adversos , Federação Russa , Resultado do Tratamento , Zidovudina/administração & dosagem , Zidovudina/efeitos adversos
20.
Assay Drug Dev Technol ; 13(10): 628-37, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26690766

RESUMO

The Plasmodium falciparum telomerase reverse transcriptase (PfTERT) is a ribonucleoprotein that assists the maintenance of the telomeric ends of chromosomes by reverse transcription of its own RNA subunit. It represents an attractive therapeutic target for eradication of the plasmodial parasite at the asexual liver stage. Automated modeling using MUSTER and knowledge-based techniques were used to obtain a three-dimensional model of the active site of reverse transcriptase domain of PfTERT, which is responsible for catalyzing the addition of incoming dNTPs to the growing DNA strand in presence of divalent magnesium ions. Further, the ternary complex of the active site of PfTERT bound to a DNA-RNA duplex was also modeled using Haddock server and represents the functional form of the enzyme. Initially, established nucleoside analog inhibitors of PfTERT, AZTTP, and ddGTP were docked in the modeled binding site of the PfTERT ternary complex using AutoDock v4.2. Subsequently, docking studies were carried out with 14 approved nucleoside analog inhibitors. Docking studies predicted that floxuridine, gemcitabine, stavudine, and vidarabine have high affinity for the PfTERT ternary complex. Further analysis on the basis of known side effects led us to propose repositioning of vidarabine as a suitable drug candidate for inhibition of PfTERT.


Assuntos
Antimaláricos/farmacologia , Reposicionamento de Medicamentos/métodos , Nucleosídeos/farmacologia , Plasmodium falciparum/enzimologia , DNA Polimerase Dirigida por RNA/metabolismo , Inibidores da Transcriptase Reversa/farmacologia , Telomerase/antagonistas & inibidores , Sequência de Aminoácidos , Antimetabólitos/farmacologia , Nucleotídeos de Desoxiguanina/antagonistas & inibidores , Nucleotídeos de Desoxiguanina/genética , Didesoxinucleotídeos/antagonistas & inibidores , Didesoxinucleotídeos/genética , Humanos , Magnésio/metabolismo , Modelos Moleculares , Simulação de Acoplamento Molecular , Dados de Sequência Molecular , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/crescimento & desenvolvimento , Estrutura Terciária de Proteína , DNA Polimerase Dirigida por RNA/genética , Telomerase/genética , Nucleotídeos de Timina/antagonistas & inibidores , Nucleotídeos de Timina/genética , Vidarabina/farmacologia , Zidovudina/análogos & derivados , Zidovudina/antagonistas & inibidores
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