Kucera Louis S, Morris-Natschke Susan L, Ishaq Khalid S, Hes Jan, Iyer Nathan, Furman Phillip A, Fleming Ronald A
Wake Forest University School of Medicine, Department of Microbiology and Immunology, Winston-Salem, North Carolina 27157-1064, USA.
Nucleosides Nucleotides Nucleic Acids. 2004;23(1-2):385-99. doi: 10.1081/ncn-120028335.
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.
对合成的磷胆碱脂质-AZT共轭物INK-20进行了评估，以检测其对野生型HIV-1、一对匹配的AZT治疗前和治疗后的临床分离株以及多药耐药临床分离株的抗病毒活性。此外，还使用针对感染性病毒增殖的合胞体空斑减少试验，检测了INK-20对耐核苷（AZT、3TC）和非核苷（奈韦拉平）逆转录酶及蛋白酶（沙奎那韦）抑制剂的病毒的活性。INK-20和AZT对野生型HIV-1的半数有效浓度（EC50）值分别为0.004和0.005微摩尔。在CEM-SS细胞和包括外周血单核细胞（PBMC）在内的其他四种细胞类型中进行检测时，INK-20显示出极小的细胞毒性或无细胞毒性。这使得INK-20和AZT的选择性指数分别大于25000和大于20000。在针对一对匹配的AZT治疗前和治疗后的临床分离株进行检测时，INK-20的EC50值分别为0.01和0.03微摩尔，AZT的EC50值分别为0.0005和0.33微摩尔。与这些病毒对单独AZT的明显耐药性相比，INK-20对另外两种AZT耐药变体具有中度至良好的活性，对一种多药耐药临床分离株具有非常好的活性。INK-20对耐3TC、奈韦拉平和沙奎那韦的病毒仍保持显著活性。合成的磷胆碱脂质-AZT共轭物INK-20代表了一类新型抗HIV化合物，可能为治疗HIV耐药变体提供新策略。
