Schols D, Struyf S, Van Damme J, Esté J A, Henson G, De Clercq E
Laboratory of Experimental Chemotherapy, Rega Institute for Medical Research, Leuven, Belgium.
J Exp Med. 1997 Oct 20;186(8):1383-8. doi: 10.1084/jem.186.8.1383.
Bicyclams are a novel class of antiviral compounds that are highly potent and selective inhibitors of the replication of HIV-1 and HIV-2. Surprisingly, however, when the prototype compound AMD3100 was tested against M-tropic virus strains such as BaL, ADA, JR-CSF, and SF-162 in human peripheral blood mononuclear cells, the compound was completely inactive. Because of the specific and potent inhibitory effect of AMD3100 on T-tropic viruses, but not M-tropic viruses, it was verified that AMD3100 interacts with the CXC-chemokine receptor CXCR4, the main coreceptor used by T-tropic viruses. AMD3100 dose dependently inhibited the binding of a specific CXCR4 monoclonal antibody to SUP-T1 cells as measured by flow cytometry. It did not inhibit the binding of the biotinylated CC-chemokine macrophage inflammatory protein (MIP) 1alpha or MIP-1beta, ligands for the chemokine receptor CCR5 (the main coreceptor for M-tropic viruses). In addition, AMD3100 completely blocked (a) the Ca2+ flux at 100 ng/ml in lymphocytic SUP-T1 and monocytic THP-1 cells, and (b) the chemotactic responses of THP-1 cells induced by stromal cell-derived factor 1alpha, the natural ligand for CXCR4. Finally, AMD3100 had no effect on the Ca2+ flux induced by the CC-chemokines MIP-1alpha, regulated on activation normal T cell expressed and secreted (RANTES; also a ligand for CCR5), or monocyte chemoattractant protein 3 (a ligand for CCR1 and CCR2b), nor was it able to induce Ca2+ fluxes by itself. The bicyclams are, to our knowledge, the first low molecular weight anti-HIV agents shown to act as potent and selective CXCR4 antagonists.
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。然而，令人惊讶的是，当原型化合物AMD3100在人外周血单核细胞中针对M嗜性病毒株（如BaL、ADA、JR-CSF和SF-162）进行测试时，该化合物完全无活性。由于AMD3100对T嗜性病毒具有特异性和强效抑制作用，而对M嗜性病毒无此作用，因此证实AMD3100与CXC趋化因子受体CXCR4相互作用，CXCR4是T嗜性病毒使用的主要共受体。通过流式细胞术测量，AMD3100剂量依赖性地抑制特异性CXCR4单克隆抗体与SUP-T1细胞的结合。它不抑制生物素化的CC趋化因子巨噬细胞炎性蛋白（MIP）1α或MIP-1β（趋化因子受体CCR5的配体，M嗜性病毒的主要共受体）的结合。此外，AMD3100完全阻断了：（a）淋巴细胞SUP-T1和单核细胞THP-1细胞中100 ng/ml时的Ca2+通量，以及（b）基质细胞衍生因子1α（CXCR4的天然配体）诱导的THP-1细胞的趋化反应。最后，AMD3100对CC趋化因子MIP-1α、活化正常T细胞表达和分泌调节因子（RANTES；也是CCR5的配体）或单核细胞趋化蛋白3（CCR1和CCR2b的配体）诱导的Ca2+通量没有影响，其自身也不能诱导Ca2+通量。据我们所知，双环胺类是首批显示出作为强效和选择性CXCR4拮抗剂的低分子量抗HIV药物。
