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1.
J Virol ; 85(2): 1077-85, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21084491

RESUMO

Langerhans cells (LCs) and interstitial dendritic cells (IDCs) may be among the first human immunodeficiency virus type 1 (HIV-1) targets after sexual transmission. We generated cells of these types by differentiation of purified CD34(+) cord blood cells. After in vitro infection with R5-tropic strains, we obtained similar percentages of infected cells for both dendritic cell (DC) subsets. Moreover, LC infection was not increased by blockage of langerin by antilangerin. These results indicate that, under our experimental conditions, there was no evidence of any preference of HIV replication in LCs versus IDCs. The inhibitory activity of HIV-1-specific IgAs and IgGs against HIV-1 replication in LCs and IDCs was analyzed. We found that neutralizing antibodies inhibit HIV-1 infection of both DC subsets. Interestingly, HIV-1 was inhibited more efficiently by the IgGs than the corresponding IgA, due to an Fcγ receptor-dependent mechanism. Moreover, nonneutralizing inhibitory IgGs were able to inhibit infection of both LCs and IDCs. These results underline the importance of HIV-1 inhibition by the binding of the Fc part of IgGs to Fcγ receptors and suggest that the induction of neutralizing and nonneutralizing inhibitory IgGs in addition to neutralizing IgAs at mucosal sites may contribute to protection against sexual transmission of HIV-1.


Assuntos
Anticorpos Neutralizantes/imunologia , Células Dendríticas/virologia , Anticorpos Anti-HIV/imunologia , HIV-1/patogenicidade , Células de Langerhans/virologia , Células Cultivadas , Citometria de Fluxo , HIV-1/crescimento & desenvolvimento , HIV-1/imunologia , Humanos , Imunoglobulina A/imunologia , Imunoglobulina G/imunologia
2.
Nucleic Acids Symp Ser (Oxf) ; (52): 539-40, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18776492

RESUMO

Synthesis, in vitro anti-HIV activity, stability studies as well as potential for oral absorption of some novel phenyl S-acyl-2-thioethyl (SATE) phosphotriester derivatives of AZT (zidovudine; 3'-azido-2',3'- dideoxythymidine) are reported herein. These mononucleotide prodrugs (pronucleotides) are characterized by the presence of polar (amino or hydroxyl) functions on the SATE biolabile phosphate protections. Whereas pronucleotides incorporating an amino residue in the vicinity of the thioester functionality display low chemical stability, the introduction of one or two hydroxyl groups on the SATE moiety confers high resistance of the resulting prodrugs towards esterase hydrolysis. Thus, one of these pronucleotides, derivative 2, was able to cross a Caco-2 cell monolayer mainly in intact form, probing that its further development is warranted as a possible HIV-pronucleotide candidate.


Assuntos
Fármacos Anti-HIV/química , Pró-Fármacos/química , Zidovudina/análogos & derivados , Fármacos Anti-HIV/metabolismo , Fármacos Anti-HIV/farmacologia , Transporte Biológico Ativo , Células CACO-2 , Linhagem Celular , HIV-1/efeitos dos fármacos , HIV-1/fisiologia , Meia-Vida , Humanos , Pró-Fármacos/metabolismo , Pró-Fármacos/farmacologia , Nucleotídeos de Pirimidina/química , Nucleotídeos de Pirimidina/metabolismo , Nucleotídeos de Pirimidina/farmacologia , Replicação Viral
3.
Gastroenterol Clin Biol ; 32(1 Pt. 1): 59-68, 2008 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-18341978

RESUMO

AIM: Infection with hepatitis C virus (HCV) results in chronic hepatitis in more than 70% of cases. Alterations in the maturation of dendritic cells (DC) might play a role in the immune system's inability to eliminate the virus, although viral factors that could be involved have not been identified. This study in vitro investigated whether HCV structural proteins affect maturation of monocyte-derived DC. METHODS: HCV proteins (core, E1, E2) were expressed by transduction with recombinant adenoviruses of immature DC. The ability of these transduced DC to respond to a maturation stimulus was evaluated by measuring cell surface markers, allogenic lymphocyte stimulation and interleukin (IL)-12 production. RESULTS: Expression of HCV structural proteins did not modify DC maturation in the presence of lipopolysaccharide, as determined by their phenotype and stimulatory functioning. IL-12 secretion was not affected by HCV protein expression in mature DC. CONCLUSION: Our results suggest that HCV structural proteins do not affect maturation of monocyte-derived DC by lipopolysaccharide. These findings are important for further studies to clarify the pathogenesis of chronic HCV infection and towards the rational design of cellular vaccine approaches for immunotherapy against hepatitis C.


Assuntos
Células Dendríticas/imunologia , Hepacivirus/imunologia , Proteínas Estruturais Virais/imunologia , Antígenos de Superfície/imunologia , Diferenciação Celular/imunologia , Processos de Crescimento Celular/imunologia , Células Cultivadas , Humanos , Interleucina-12/imunologia , Interleucina-8/imunologia , Lipopolissacarídeos/imunologia , Ativação Linfocitária/imunologia , Monócitos/imunologia , Fenótipo , Transdução Genética , Proteínas do Core Viral/imunologia , Proteínas do Envelope Viral/imunologia
4.
J Virol ; 81(24): 13865-75, 2007 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17898067

RESUMO

Simian immunodeficiency virus (SIV) infection of rhesus macaques (RMs) provides a reliable model to study the relationship between lentivirus replication, cellular immune responses, and CD4+ T-cell dynamics. Here we investigated, using SIVmac251-infected RMs of a Chinese genetic background (which experience a slower disease progression than Indian RMs), the dynamics of CD4+ CCR5+ T cells, as this subset of memory/activated CD4+ T cells is both a preferential target of virus replication and a marker of immune activation. As expected, we observed that the number of circulating CD4+ CCR5+ T cells decreases transiently at the time of peak viremia. However, at 60 days postinfection, i.e., when set-point viremia is established, the level of CD4+ CCR5+ T cells was increased compared to the baseline level. Interestingly, this increase correlated with faster disease progression, higher plasma viremia, and early loss of CD4+ T-cell function, as measured by CD4+ T-cell count, the fraction of memory CD4+ T cells, and the recall response to purified protein derivative. Taken together, these data show a key difference between the dynamics of the CD4+ CCR5+ T-cell pool (and its relationship with disease progression) in Chinese RMs and those described in previous reports for Indian SIVmac251-infected RMs. As the SIV-associated changes in the CD4+ CCR5+ T-cell pool reflect the opposing forces of SIV replication (which reduces this cellular pool) and immune activation (which increases it), our data suggest that in SIV-infected Chinese RMs the impact of immune activation is more prominent than that of virus replication in determining the size of the pool of CD4+ CCR5+ T cells in the periphery. As progression of HIV infection in humans also is associated with a relative expansion of the level of CD4+ CCR5+ T cells, we propose that SIV infection of Chinese RMs is a very valuable and important animal model for understanding the pathogenesis of human immunodeficiency virus infection.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Modelos Animais de Doenças , Receptores CCR5/metabolismo , Síndrome de Imunodeficiência Adquirida dos Símios/imunologia , Síndrome de Imunodeficiência Adquirida dos Símios/fisiopatologia , Vírus da Imunodeficiência Símia/imunologia , Animais , China , Progressão da Doença , Memória Imunológica , Ativação Linfocitária , Macaca mulatta , RNA Viral/sangue , Síndrome de Imunodeficiência Adquirida dos Símios/virologia , Vírus da Imunodeficiência Símia/patogenicidade , Vírus da Imunodeficiência Símia/fisiologia , Replicação Viral
5.
Arch Virol ; 152(3): 507-18, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17122895

RESUMO

PHA-stimulated peripheral blood mononuclear cells (PBMCs) are widely used for investigating replication and neutralization of HIV primary isolates in vitro. The objective of this study was to identify the T lymphocyte subset(s) that are found infected after one replication cycle by either R5- or X4-HIV-1 variants in PHA-stimulated PBMCs from healthy donors. Infected T lymphocytes were detected by intracellular p24 staining and characterized by cell surface immunophenotyping using flow cytometry. The predominant lymphocyte subset expressing p24 after 24 h of infection with either R5 or X4 HIV-1 strains was found to exhibit mainly the memory CD45RO phenotype, a greater percentage of CD62L(+)CD45RO(+) central memory T lymphocytes was infected with X4 HIV strains. Although some CD45RA(+) lymphocytes were also infected, these cells co-expressed CD45RO(+). The proportion of lymphocytes expressing CD4 and CD4/CD45RO decreased by 20% after 24 h of infection. A 2-fold decrease of CD4(+)CD8(+) T lymphocytes could also be recorded, even though this subset accounted for less than 5% of total lymphocytes in control cultures. Moreover, CD4(+)CD8(+) T cells further decreased by 90% after 4 days of infection, a time at which they scored p24(+). Therefore, our results indicate that the in vitro infection system of PHA-stimulated PBMC utilized in neutralization assays provides an appropriate model for the study of infected CD45RO(+) lymphocytes but not CD45RA(+) lymphocytes.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Infecções por HIV/imunologia , HIV-1/genética , HIV-1/patogenicidade , Antígenos Comuns de Leucócito/imunologia , Leucócitos Mononucleares/virologia , Linfócitos T CD4-Positivos/virologia , Variação Genética , HIV-1/classificação , Antígenos HLA-A/sangue , Antígenos HLA-B/sangue , Antígenos HLA-C/sangue , Humanos , Leucócitos Mononucleares/imunologia , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Valores de Referência
6.
7.
Artigo em Inglês | MEDLINE | ID: mdl-14565300

RESUMO

Expected for the ability to inhibit HIV replication, we report the synthesis of two heterodimers of the general formula: [2NRTI]-C5-GLY-SUCCINYL-Npiperazinyl-[NNRTI] (18, 19) containing both a Nucleoside Reverse Transcriptase Inhibitor (10, 11) and a Non-Nucleoside Reverse Transcriptase Inhibitor (8) [Trovirdine Analogue belonging of the phenethyl thiazolyl thiourea class] connected through the "succinyl-glycine" spontaneously cleavable linker.


Assuntos
HIV-1/fisiologia , Inibidores da Transcriptase Reversa/síntese química , Replicação Viral/efeitos dos fármacos , Dimerização , HIV-1/efeitos dos fármacos , Indicadores e Reagentes , Modelos Moleculares , Estrutura Molecular , Piridinas/química , Inibidores da Transcriptase Reversa/farmacologia
8.
Nucleosides Nucleotides Nucleic Acids ; 22(5-8): 899-901, 2003.
Artigo em Inglês | MEDLINE | ID: mdl-14565306

RESUMO

The synthesis and the study of two phosphorothiolate derivatives of 3'-azido-2',3'-dideoxythymidine (AZT) bearing a S-pivaloyl-2-thioethyl (tBuSATE) group and glucosyl residues associated to the phosphorus atom by a 2-oxyethyl link, are reported. These derivatives could be considered as prototypes of a new series of nucleotide prodrugs (pronucleotides).


Assuntos
Antivirais/síntese química , Nucleosídeos/síntese química , Pró-Fármacos/síntese química , Zidovudina/síntese química , Antivirais/química , Estrutura Molecular , Nucleosídeos/farmacologia , Pró-Fármacos/química , Zidovudina/análogos & derivados , Zidovudina/química
9.
Artigo em Inglês | MEDLINE | ID: mdl-14565307

RESUMO

Synthesis and biological activities of several phosphotriester derivatives of 3'-azido-2',3'-dideoxythymidine (AZT) bearing a S-pivaloyl-2-thioethyl (tBuSATE) group and aryl residues derived from L-tyrosine are reported. All compounds showed marked anti-HIV activity in thymidine kinase-deficient CEM cells demonstrating their ability to deliver intracellularly the parent 5'-mononucleotide.


Assuntos
Fármacos Anti-HIV/síntese química , HIV/efeitos dos fármacos , Zidovudina/análogos & derivados , Fármacos Anti-HIV/farmacocinética , Fármacos Anti-HIV/farmacologia , Transporte Biológico , Linhagem Celular , Didesoxinucleotídeos , Humanos , Estrutura Molecular , Timidina Quinase/deficiência , Nucleotídeos de Timina/farmacocinética , Zidovudina/síntese química , Zidovudina/farmacocinética , Zidovudina/farmacologia
10.
Artigo em Inglês | MEDLINE | ID: mdl-14565305

RESUMO

The synthesis, anti-HIV activity and stability studies of a H-phosphonamidate derivative of 3'-azido-2',3'-dideoxythymidine (AZT) incorporating a N,N-diisopropylamino residue as first model of alkylamino group are reported. The results demonstrate that such phosphorylated structure exerts its biological effects via chemical hydrolysis into the corresponding H-phosphonate, precursor of the parent nucleoside.


Assuntos
Fármacos Anti-HIV/síntese química , HIV/efeitos dos fármacos , Nucleosídeos/síntese química , Nucleotídeos/síntese química , Pró-Fármacos/síntese química , Zidovudina/análogos & derivados , Zidovudina/síntese química , Linhagem Celular , Desenho de Fármacos , Estabilidade de Medicamentos , Humanos , Hidrólise , Estrutura Molecular , Organofosfonatos , Linfócitos T
11.
Artigo em Inglês | MEDLINE | ID: mdl-12484448

RESUMO

A series of eleven heterodimers containing both a nucleoside analogue (d4U, d4T) and a non-nucleoside type inhibitor (Trovirdine analogue) were synthesized and evaluated for their ability to inhibit HIV replication. Unfortunately, the (N-3)d4U-Trovirdine conjugates (9a-e) and (N-3)d4T-Trovirdine conjugates (10a-f) were found to be inactive suggesting that the two individual inhibitor compounds do not bind simultaneously in their respective sites.


Assuntos
Didesoxinucleosídeos/síntese química , Transcriptase Reversa do HIV/antagonistas & inibidores , Piridinas/síntese química , Inibidores da Transcriptase Reversa/síntese química , Estavudina/síntese química , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Didesoxinucleosídeos/química , Didesoxinucleosídeos/farmacologia , Dimerização , Avaliação Pré-Clínica de Medicamentos , HIV-1/efeitos dos fármacos , HIV-1/enzimologia , Humanos , Linfócitos/efeitos dos fármacos , Linfócitos/enzimologia , Linfócitos/virologia , Piridinas/química , Piridinas/farmacologia , Inibidores da Transcriptase Reversa/química , Inibidores da Transcriptase Reversa/farmacologia , Estavudina/química , Estavudina/farmacologia , Células Tumorais Cultivadas , Zidovudina/farmacologia
12.
Arch Virol ; 147(10): 1963-75, 2002 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-12376757

RESUMO

The nef genes of human and simian immunodeficiency viruses code for a membrane associated protein critical for AIDS development. SIVmac Nef presents C-terminal a 27 amino acid extension absent of HIV-1 Nef. To estimate the influence of this C-terminal domain on virus properties, we constructed viruses derived from SIVmac239 by replacing SIV nef with HIV-1 Lai nef gene (SHIV NefLai4) or with a sequence encoding a Nef fusion protein: HIV-1 Lai Nef/SIV Nef-Cterm (SHIV-Cterm). The recombinant viruses replicated efficiently in vitro in CEMx174 cells and in activated macaque PBMCs. The addition of SIV Nef C-terminal domain to HIV-1 Nef in SHIVNefLai4 did not change the in vitro properties of the chimeric virus, both viruses being more infectious than a nef deleted virus. Although the half-life of Nef fusion protein was augmented, SHIV-Cterm remained slightly less infectious than SIVmac239.


Assuntos
Genes nef , HIV-1/genética , Proteínas Recombinantes de Fusão/biossíntese , Vírus da Imunodeficiência Símia/genética , Proteínas Virais Reguladoras e Acessórias/genética , Sequência de Aminoácidos , Animais , HIV-1/patogenicidade , Macaca , Dados de Sequência Molecular , Vírus da Imunodeficiência Símia/patogenicidade , Proteínas Virais Reguladoras e Acessórias/biossíntese , Proteínas Virais Reguladoras e Acessórias/química , Replicação Viral
13.
Cell Mol Life Sci ; 59(12): 2184-90, 2002 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-12568344

RESUMO

Transplantation of organs, tissues or cells from pigs to humans could be a potential solution to the shortage of human organs for transplantation. Porcine endogenous retroviruses (PERVs) remain a major safety concern for porcine xenotransplantation. Thus, finding drugs that could be used as virological prophylaxis (or therapy) against PERV replication would be desirable. One of the most effective ways to block retroviral multiplication is to inhibit the enzyme reverse transcriptase (RT) which catalyzes the reverse transcription of viral RNA to proviral double-stranded DNA. We report here the cloning and expression of PERV RT and its susceptibility to several inhibitors. Our data demonstrate PERV susceptibility in vitro to the triphosphorylated nucleoside analog of zidovudine (AZT) and to ddGTP and to a lesser extent to ddTTP but almost no susceptibility to the non-nucleoside RT inhibitors tested.


Assuntos
Retrovirus Endógenos/enzimologia , Nucleosídeos/metabolismo , DNA Polimerase Dirigida por RNA/metabolismo , Inibidores da Transcriptase Reversa/farmacologia , Sequência de Aminoácidos , Animais , Cloretos/metabolismo , Clonagem Molecular , DNA Polimerase Dirigida por DNA/metabolismo , Humanos , Cloreto de Magnésio/metabolismo , Compostos de Manganês/metabolismo , Dados de Sequência Molecular , Estrutura Molecular , Nucleosídeos/química , DNA Polimerase Dirigida por RNA/química , DNA Polimerase Dirigida por RNA/genética , Proteínas Recombinantes/metabolismo , Ribonuclease H/metabolismo , Cloreto de Sódio/metabolismo , Suínos
14.
Carbohydr Res ; 336(3): 161-80, 2001 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-11705466

RESUMO

With the aim at improving the transport of the current HIV protease inhibitors across the intestinal and blood brain barriers and their penetration into the central nervous system, the synthesis of various acyl and carbamatoyl glucose-containing prodrugs derived from saquinavir, indinavir and nelfinavir, their in vitro stability with respect to hydrolysis, and their anti-HIV activity have been investigated. D-Glucose, which is actively transported across these barriers, was connected through its 3-hydroxyl to these antiproteases via a linker. The liberation of the active free drug during the incubation time of the prodrugs with the cells was found to be crucial for HIV inhibition. The labile ester linking of the glucose-containing moiety to the peptidomimetic hydroxyl of saquinavir or to the indinavir C-8 hydroxyl, which is not part of the transition state isostere, is not an obstacle for anti-HIV activity. This is not the case for its stable carbamate linking to the peptidomimetic hydroxyl of saquinavir, indinavir and nelfinavir. The chemical stability with respect to hydrolysis of some of the saquinavir and indinavir prodrugs reported here, the liberation rate of the active free drug and the HIV inhibitory potency are acceptable for an in vivo use of these prodrugs. These glucose-linked ester and carbamate prodrugs display a promising therapeutic potential provided that their bioavailability, penetration into the HIV sanctuaries, and/or the liberation of the active free drug from the carbamate prodrugs are improved. Furthermore, no cytotoxicity was detected for the prodrugs for concentrations as high as 10 or even 100 microM, thus indicating an encouraging therapeutic index.


Assuntos
Inibidores da Protease de HIV/síntese química , Inibidores da Protease de HIV/farmacocinética , Pró-Fármacos/síntese química , Pró-Fármacos/farmacocinética , Carbamatos/síntese química , Carbamatos/farmacocinética , Sobrevivência Celular/efeitos dos fármacos , Reagentes de Ligações Cruzadas/química , Ésteres/síntese química , Ésteres/farmacocinética , Glucose/química , Glucose/farmacocinética , Inibidores da Protease de HIV/farmacologia , HIV-1/efeitos dos fármacos , HIV-1/crescimento & desenvolvimento , Meia-Vida , Humanos , Hidrólise , Indinavir/química , Indinavir/farmacocinética , Indinavir/farmacologia , Nelfinavir/química , Nelfinavir/farmacocinética , Nelfinavir/farmacologia , Pró-Fármacos/farmacologia , Saquinavir/química , Saquinavir/farmacocinética , Saquinavir/farmacologia , Células Tumorais Cultivadas
15.
Nucleosides Nucleotides Nucleic Acids ; 20(9): 1655-70, 2001 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-11580192

RESUMO

The target compounds 5-[N-(6-amino-hexyl)-acrylamide]-2',3'-didehydro-2',3'-dideoxy-uridine (12) and 5-[N-[5-(methoxycarbonyl)-pentyl]-acrylamide]-2',3'-didehydro-2',3'- dideoxy-uridine (15) were prepared by the palladium acetate-triphenylphosphine-catalyzed reaction of the 5'-O-acetyl-5-iodo-d4T analogue (3). These compounds 12 and 15 can be used to prepare nucleotide probes carrying fluorescent labels and were nevertheless screened for their anti-HIV activity. The biological data demonstrated that none of them were active against HIV-1.


Assuntos
Paládio/química , Estavudina/análogos & derivados , Estavudina/síntese química , Uridina/análogos & derivados , Uridina/síntese química , Catálise/efeitos dos fármacos , Linhagem Celular , Cromatografia em Camada Fina , HIV-1/efeitos dos fármacos , HIV-1/enzimologia , HIV-1/fisiologia , Humanos , Espectroscopia de Ressonância Magnética , Paládio/farmacologia , DNA Polimerase Dirigida por RNA/metabolismo , Espectroscopia de Infravermelho com Transformada de Fourier , Estavudina/química , Estavudina/farmacologia , Uridina/química , Uridina/farmacologia , Zidovudina/farmacologia
16.
Artigo em Inglês | MEDLINE | ID: mdl-11563043

RESUMO

Synthesis, biological activities and decomposition kinetics of novel phosphotriester derivatives of 3'-azido-2',3'-dideoxythymidine (AZT) bearing a S-tButyl-2-thioethyl (tBuSATE) group and L-tyrosinyl residues are reported. All the derivatives appeared to be potent inhibitors of HIV-1 replication in various cell culture experiments. The proposed decomposition process of these mixed phosphotriesters may involve successively an esterase and then a phosphodiesterase activation.


Assuntos
Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/farmacologia , Pró-Fármacos/síntese química , Pró-Fármacos/farmacologia , Zidovudina/análogos & derivados , Fármacos Anti-HIV/química , Células Cultivadas , Desenho de Fármacos , Estabilidade de Medicamentos , Ésteres/síntese química , Ésteres/química , Ésteres/farmacologia , HIV-1/efeitos dos fármacos , HIV-1/fisiologia , Humanos , Pró-Fármacos/química , Replicação Viral/efeitos dos fármacos , Zidovudina/síntese química , Zidovudina/farmacologia
17.
Artigo em Inglês | MEDLINE | ID: mdl-11563108

RESUMO

The synthesis and the study of new mononucleoside phosphoramidate diesters bearing S-acyl-2-thioethyl (SATE) groups and an alkylamino residue are reported. The studied compounds appear to be able to deliver the corresponding 5'-mononucleotide inside the cells, and could be considered as prototypes for a new kind of mononucleotide prodrugs (pronucleotides).


Assuntos
Amidas/síntese química , Fármacos Anti-HIV/síntese química , Nucleotídeos/síntese química , Ácidos Fosfóricos/síntese química , Pró-Fármacos/síntese química , Amidas/farmacocinética , Amidas/farmacologia , Fármacos Anti-HIV/farmacocinética , Fármacos Anti-HIV/farmacologia , Humanos , Nucleotídeos/farmacocinética , Nucleotídeos/farmacologia , Ácidos Fosfóricos/farmacocinética , Ácidos Fosfóricos/farmacologia , Pró-Fármacos/farmacocinética , Pró-Fármacos/farmacologia
18.
Eur J Med Chem ; 36(5): 447-60, 2001 May.
Artigo em Inglês | MEDLINE | ID: mdl-11451533

RESUMO

In the search for new chemotherapeutic agents, we have focused our work on the synthesis and the study of several unnatural beta-L-nucleoside analogues. In this paper, we report on the synthesis of beta-L-pentofuranonucleosides (and their 2'-deoxy derivatives) of 5-fluorouracil and their inhibitory effects on the proliferation of several murine and human tumor cells. The corresponding 5-fluorocytosine derivatives were also synthesized and their anti-HIV and anti-HBV activities have been evaluated.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Flucitosina/análogos & derivados , Fluoruracila/análogos & derivados , Nucleosídeos/síntese química , Nucleosídeos/farmacologia , Animais , Fármacos Anti-HIV/farmacologia , Antineoplásicos/química , Antineoplásicos/toxicidade , Divisão Celular/efeitos dos fármacos , Desenho de Fármacos , HIV/efeitos dos fármacos , Humanos , Camundongos , Nucleosídeos/química , Nucleosídeos/toxicidade , Estereoisomerismo , Relação Estrutura-Atividade , Linfócitos T/citologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Células Tumorais Cultivadas
19.
J Med Chem ; 44(13): 2188-203, 2001 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-11405656

RESUMO

We describe the synthesis together with the results of anti-HIV-1 activity and gp120-monolayer binding experiments of new galactosyl amphiphiles, analogues of galactosylceramide, an alternative receptor used by HIV to infect CD4 negative cells. These compounds consist of single- and double-chain amphiphiles containing one or two galactose residues. To favor their clustering into galactosyl-rich microdomains, their molecular structure contains also an amino group or several hydroxyls or anionic groups, such as carboxylate, sulfate, sulfonate, and phosphate. Among the 12 new galactosylated compounds reported, a specific anti-HIV activity, although moderate (IC(50) from 10 to 50 microM), was detected only for three of them, i.e., I-GalSer[CO2Na][C14], II-GalSer[C14][C7SO3Na], and II-GalSer[C2SO4Na][C14], which contain an anionic group. The marked increase of surface pressure which was observed upon addition of gp120 into the aqueous subphase underneath the monolayers containing these galactolipids indicated gp120 insertion into the monolayers, suggesting that binding of these three derivatives to HIV-1 gp120 may be responsible for their anti-HIV activity.


Assuntos
Fármacos Anti-HIV/síntese química , Galactosilceramidas/síntese química , Proteína gp120 do Envelope de HIV/metabolismo , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Células Cultivadas , Galactosilceramidas/química , Galactosilceramidas/metabolismo , Galactosilceramidas/farmacologia , Humanos , Testes de Sensibilidade Microbiana , Ligação Proteica , Relação Estrutura-Atividade
20.
J Virol ; 75(11): 5421-4, 2001 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-11333928

RESUMO

The factors present in serum and plasma samples of human immunodeficiency virus (HIV)-infected patients that are responsible for the neutralization of four HIV type 1 (HIV-1) primary isolates in vitro have been analyzed. Purification of immunoglobulins (Ig) by affinity chromatography showed that the activities were mostly attributable to IgG and less frequently to IgA. For two samples, we have shown that the high-level and broad-spectrum inhibitory activity was essentially caused by non-Ig factors interfering with the measurement of antibody-specific neutralizing activity.


Assuntos
Anticorpos Anti-HIV/análise , Infecções por HIV/imunologia , HIV-1/imunologia , Imunoglobulina A/análise , Imunoglobulina G/análise , Infecções por HIV/virologia , Humanos , Soros Imunes , Masculino , Testes de Neutralização
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