Synthesis and Evaluation of a Novel Synthetic Phosphocholine Lipid-AZT Conjugate That Double-Targets Wild-Type and Drug Resistant Variants of HIV †.

Autor: Kucera, LouisS., Morris‐Natschke, SusanL., Ishaq, KhalidS., Hes, Jan, Iyer, Nathan, Furman, PhillipA., Fleming, RonaldA.
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Zdroj: Nucleosides, Nucleotides & Nucleic Acids; Jan2004, Vol. 23 Issue 1/2, p385-399, 15p, 4 Diagrams, 4 Charts
Abstrakt: 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 multi-drug 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 EC[sub50] values were 0.004, and 0.005 µM 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 EC[sub50] values were 0.01 and 0.03 µM for INK-20 and 0.0005 and 0.33 µM 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. [ABSTRACT FROM AUTHOR]
Databáze: Complementary Index
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