Schols D, Esté J A, Henson G, De Clercq E
Rega Institute for Medical Research, Leuven, Belgium.
Antiviral Res. 1997 Aug;35(3):147-56. doi: 10.1016/s0166-3542(97)00025-9.
Bicyclams are a novel class of antiviral compounds which are highly potent and selective inhibitors of the replication of HIV-1 and HIV-2. The prototype compound, AMD3100, has an IC50 of 1-10 ng/ml, which is a least 100,000 fold lower than the cytotoxic concentration. AMD3100 does not inhibit virus binding to the CD4 receptor and based on time-of-addition experiments, has been assumed to interact with the HIV fusion-uncoating process. Resistance of HIV-1 strains to AMD3100 is associated with the accumulation of several mutations in the viral envelope glycoprotein gp120. Here, we demonstrate that AMD3100 interacts with fusin (CXCR-4), the coreceptor used by T-tropic viruses to infect the target cells. The replication of NL4-3 wild type virus and NL4-3 dextran sulfate-resistant virus was inhibited by the CXC-chemokine, stromal cell-derived factor 1 (SDF-1), the natural ligand for CXCR-4. In contrast, the replication of the HIV-1 NL4-3 AMD3100-resistant virus was no longer inhibited by SDF-1. The bicyclams are the first low-molecular-weight anti-HIV agents shown to interact with the coreceptor for T-tropic viruses.
双环胺类是一类新型抗病毒化合物，是HIV-1和HIV-2复制的高效且选择性抑制剂。原型化合物AMD3100的半数抑制浓度（IC50）为1-10纳克/毫升，比细胞毒性浓度至少低10万倍。AMD3100不抑制病毒与CD4受体的结合，基于添加时间实验，推测其与HIV融合-脱壳过程相互作用。HIV-1毒株对AMD3100的耐药性与病毒包膜糖蛋白gp120中多个突变的积累有关。在此，我们证明AMD3100与趋化因子（CXCR-4）相互作用，CXCR-4是T嗜性病毒用来感染靶细胞的共受体。NL4-3野生型病毒和NL4-3抗硫酸葡聚糖病毒的复制受到CXCR-4的天然配体CXC趋化因子基质细胞衍生因子1（SDF-1）的抑制。相反，HIV-1 NL4-3 AMD3100耐药病毒的复制不再受SDF-1抑制。双环胺类是首个被证明与T嗜性病毒共受体相互作用的低分子量抗HIV药物。
