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1.
J Antimicrob Chemother ; 51(4): 813-9, 2003 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-12654739

RESUMO

OBJECTIVES: Given that the guanosine-quadruplex may have a role in blocking the interaction between gp120 and CD4, we describe here the design of a highly nuclease-resistant dimeric hairpin guanosine-quadruplex, [Gm3Um4Gm3-s], containing the 2'-O-methyl groups on the nucleoside and sulphur groups on the internucleotidic bonds, and its anti-HIV-1 activity in cultured cells. METHODS: The unmodified and modified oligonucleotides were chemically synthesized. The anti-HIV activities of test compounds on HIV-1 infection were determined by protection against HIV-1-induced cytopathic effects. The mechanism of action of the oligonucleotides was determined by virus binding and detection [anti-CD4 monoclonal antibody (MAb) and anti-V3 MAb] assays. RESULTS: Gm3Um4Gm3-s was highly nuclease resistant, had significantly higher anti-HIV-1 activity than dG3T4G3-s, dG10-s and Gm10-s, and blocked the interaction between gp120 and CD4. CONCLUSION: The anti-HIV-1 activity of this oligonucleotide was increased when the phosphodiester and 2'-hydroxyl groups on the oligonucleotide backbones were replaced with a phosphorothioate and 2'-O-methyl backbone; thus Gm3Um4Gm3-s may inhibit HIV-1 infection, at least in part, by blocking the interaction between gp120 and CD4.


Assuntos
Fármacos Anti-HIV/farmacologia , Guanosina/análogos & derivados , HIV-1/efeitos dos fármacos , Oligonucleotídeos/farmacologia , Replicação Viral/efeitos dos fármacos , Fármacos Anti-HIV/síntese química , Antígenos CD4/metabolismo , Células Cultivadas , Primers do DNA/síntese química , Primers do DNA/farmacologia , Exonucleases/metabolismo , Citometria de Fluxo , Proteína gp120 do Envelope de HIV/metabolismo , Vírus Linfotrópico T Tipo 1 Humano/efeitos dos fármacos , Humanos , Ensaios de Proteção de Nucleases , Oligonucleotídeos/síntese química , Ligação Proteica , Uridina
2.
J Virol ; 76(6): 3015-22, 2002 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-11861867

RESUMO

An oligonucleotide with a dimeric hairpin guanosine quadruplex (basket type structure) (dG3T4G3-s), containing phosphorothioate groups, was able to inhibit human immunodeficiency virus type 1 (HIV-1)-induced syncytium formation and virus production (as measured by p24 core antigen expression) in peripheral blood mononuclear cells. This oligonucleotide lacks primary sequence homology with the complementary (antisense) sequences to the HIV-1 genome. Furthermore, this oligonucleotide may have increased nuclease resistance. The activity of this oligonucleotide was increased when the phosphodiester backbone was replaced with a phosphorothioate backbone. In vivo results showed that dG3T4G3-s was capable of blocking the interaction between gp120 and CD4. We also found that dG3T4G3-s specifically inhibits the entry of T-cell line-tropic HIV-1 into cells. This compound is a viable candidate for evaluation as a therapeutic agent against HIV-1 in humans.


Assuntos
HIV-1/efeitos dos fármacos , Leucócitos Mononucleares/virologia , Oligonucleotídeos/química , Oligonucleotídeos/farmacologia , Células Gigantes/efeitos dos fármacos , Guanosina/química , Proteína do Núcleo p24 do HIV/efeitos dos fármacos , Infecções por HIV/virologia , HIV-1/fisiologia , Humanos , Fosfatos/química , Timidina/química
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