Kucera L S, Iyer N, Morris-Natschke S L, Chen S Y, Gumus F, Ishaq K, Herrmann D B
Wake Forest University School of Medicine, Winston-Salem, N.C., USA.
Antivir Chem Chemother. 1998 Mar;9(2):157-65. doi: 10.1177/095632029800900207.
Our laboratories first reported two novel classes of complex synthetic lipids, including alkylamidophosphocholines (PC lipid; CP-51) and alkylamidophosphate ester-linked lipid-AZT conjugates (lipid-AZT conjugates; CP-92), with selective and potent activity against human immunodeficiency virus type 1 (HIV-1). To extend these observations, we synthesized additional PC lipids and lipid-AZT conjugates (INK and INK-AZT conjugate) to evaluate their structure-activity relationships by testing for selectivity against infectious wild-type (wt) and drug-resistant HIV-1 replication, virus fusogenic activity and toxicity for mouse bone marrow cells. PC lipid compounds with medium chain lengths at positions 1 and 2 gave an improved selective index (SI). INK-3, with 12 and 8 carbons and INK-15, with 10 and 12 carbons were among the most selective when evaluated in CEM-SS cells. INK-14, a lipid-AZT conjugate where AZT replaced the choline in PC lipid INK-3, gave the highest SI of > 1250 against both infectious wt HIV-1 replication in CEM-SS cells and a clinical isolate in peripheral blood leukocytes. Notably, the PC lipid compounds INK-3 and INK-15, but not the lipid-AZT conjugate INK-14, were potent inhibitors of matched pairs of AZT-sensitive and AZT-resistant HIV-1 clinical isolates. INK-3 also inhibited replication of HIV-2 and TIBO-resistant HIV-1, and inhibited HIV-1-mediated fusogenic activity by 78, 41 and 9% in a dose-dependent manner. The TC50 for mouse bone marrow cells was > 100 micrograms/ml for INK-3 compared to 9.15-14.17 micrograms/ml for CP-51 and 0.142-0.259 microgram/ml for AZT. These data suggest that optimum PC lipid compounds are significantly less toxic than AZT and have high potential as novel therapeutic agents for AIDS.
我们的实验室首次报告了两类新型复杂合成脂质，包括烷基酰胺磷酸胆碱（PC脂质；CP - 51）和烷基酰胺磷酸酯连接的脂质 - AZT共轭物（脂质 - AZT共轭物；CP - 92），它们对1型人类免疫缺陷病毒（HIV - 1）具有选择性和强效活性。为了扩展这些观察结果，我们合成了额外的PC脂质和脂质 - AZT共轭物（INK和INK - AZT共轭物），通过测试对传染性野生型（wt）和耐药HIV - 1复制的选择性、病毒融合活性以及对小鼠骨髓细胞的毒性来评估它们的构效关系。在1位和2位具有中链长度的PC脂质化合物给出了改善的选择性指数（SI）。在CEM - SS细胞中评估时，具有12和8个碳的INK - 3以及具有10和12个碳的INK - 15是最具选择性的。INK - 14是一种脂质 - AZT共轭物，其中AZT取代了PC脂质INK - 3中的胆碱，在CEM - SS细胞中针对传染性wt HIV - 1复制以及外周血白细胞中的临床分离株给出了> 1250的最高SI。值得注意的是，PC脂质化合物INK - 3和INK - 15，但不是脂质 - AZT共轭物INK - 14，是AZT敏感和AZT耐药HIV - 1临床分离株配对的强效抑制剂。INK - 3还抑制HIV - 2和TIBO耐药HIV - 1的复制，并以剂量依赖方式将HIV - 1介导的融合活性抑制78%、41%和9%。INK - 3对小鼠骨髓细胞的TC50> 100微克/毫升，而CP - 51为9.15 - 14.17微克/毫升，AZT为0.142 - 0.259微克/毫升。这些数据表明，最佳的PC脂质化合物比AZT毒性显著更低，具有作为艾滋病新型治疗剂的高潜力。
