RESUMO
Phospholipid analogs are a new class of compounds with potent activity against HIV infection when used alone or conjugated with other therapeutic agents. When conjugated to the nucleoside analog AZT, the resulting phospholipid-AZT conjugate can double target the virus replication cycle by inhibiting the viral reverse transcriptase (by AZT) and inducing the production of defective virus particles that lack functional gp120 expression on the virus surface resulting in reduced capacity to bind to CD4+ cells and inhibition of infected cell-cell fusion (by phospholipid). Of great interest are data indicating that selected phospholipids are active against drug resistant variants, a current major problem in treating HIV/AIDS and controlling the epidemic occurring in various parts of the world. The purpose of this review is to provide current information on the design and synthesis of various types of phospholipids and phospholipid conjugates, in-vitro and in-vivo antiviral activity, tissue distribution, intracellular metabolism, and mechanism of action. The future development of this novel class of compounds offers an exciting approach for reducing the toxicity and enhancing the distribution of therapeutic drugs to the lymphatics and central nervous system and suppressing the emergence of drug resistant variants of HIV.
Assuntos
Fármacos Anti-HIV/síntese química , Infecções por HIV/tratamento farmacológico , Fosfolipídeos/síntese química , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/uso terapêutico , Ensaios Clínicos como Assunto , HIV-1/efeitos dos fármacos , HIV-1/fisiologia , Humanos , Nucleosídeos/química , Nucleosídeos/farmacologia , Nucleosídeos/uso terapêutico , Fosfolipídeos/farmacologia , Fosfolipídeos/uso terapêutico , Pró-Fármacos/síntese química , Pró-Fármacos/farmacologia , Pró-Fármacos/uso terapêutico , Distribuição Tecidual , Resultado do Tratamento , Replicação Viral/efeitos dos fármacosRESUMO
A well-defined series of 5'-([(Z)-4-amino-2-butenyl]methylamino)-5'-deoxyadenosine analogues was designed and synthesized in order to further ascertain the optimal structural requirements for S-adenosylmethionine decarboxylase inhibition and potentially to augment and perhaps separate their antiproliferative and antitrypanosomal activities. Most structural modifications had a deleterious affect on both the antitrypanosomal and antineoplastic activity of 5'-([(Z)-4-amino-2-butenyl]methylamino)-5'-deoxyadenosine. However, di-O-acetylation of the parent compound produced a potential prodrug that caused markedly pronounced inhibition of trypanosomal and neoplastic cell growth and viability. Moreover, the acetylated derivative of 5'-([(Z)-4-amino-2-butenyl]methylamino)-5'-deoxyadenosine did inhibit HIV-1 growth and infectivity, whereas the parent compound did not.
Assuntos
Fármacos Anti-HIV/síntese química , Antineoplásicos/síntese química , Desoxiadenosinas/síntese química , HIV-1/efeitos dos fármacos , Tripanossomicidas/síntese química , Adenosilmetionina Descarboxilase/antagonistas & inibidores , Adenosilmetionina Descarboxilase/química , Animais , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular , Desoxiadenosinas/química , Desoxiadenosinas/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Masculino , Camundongos , Relação Estrutura-Atividade , Tripanossomicidas/química , Tripanossomicidas/farmacologia , Trypanosoma brucei brucei/efeitos dos fármacos , Trypanosoma brucei rhodesiense/efeitos dos fármacos , Tripanossomíase/tratamento farmacológico , Células Tumorais CultivadasRESUMO
INK-20, a synthetic phosphocholine lipid-AZT conjugate, was evaluated for antiviral activity against wild-type HIV-1, a matched pair of pre-AZT and post-AZT and multidrug resistant clinical isolates. In addition, it was tested for activity against viruses resistant to nucleoside (AZT, 3TC) and nonnucleoside (nevirapine) reverse transcriptase and protease (saquinavir) inhibitors using the syncytial plaque reduction assay for infectious virus multiplication. The EC50 values were 0.004, and 0.005 microM against wild-type HIV-1 for INK-20 and AZT, respectively. INK-20 showed little or no cytotoxicity when assayed in CEM-SS cells and four other cell types including PBMC. This resulted in a selective index of > 25,000 and > 20,000 for INK-20 and AZT, respectively. When tested against a matched pair of pre-AZT and post-AZT clinical isolates, the EC50 values were 0.01 and 0.03 microM for INK-20 and 0.0005 and 0.33 microM for AZT, respectively. INK-20 had moderate to good activity against two other AZT resistant variants and very good activity against a multi-drug resistant clinical isolate compared to marked resistance of these viruses to AZT alone. INK-20 retained significant activity against viruses resistant to 3TC, nevirapine, and saquinavir. The synthetic phosphocholine lipid-AZT conjugate INK-20 represents a novel class of anti-HIV compounds, which may provide new strategies for the treatment of HIV drug-resistant variants.