Nishikawa Masao, Takashima Katsunori, Nishi Toshiya, Furuta Rika A, Kanzaki Naoyuki, Yamamoto Yoshio, Fujisawa Jun-Ichi
Department of Microbiology, Kansai Medical University, 10-15 Fumizono-cho, Moriguchi, Osaka 570-8506, Japan.
Antimicrob Agents Chemother. 2005 Nov;49(11):4708-15. doi: 10.1128/AAC.49.11.4708-4715.2005.
G protein-coupled receptor CCR5 is the main coreceptor for macrophage-tropic human immunodeficiency virus type 1 (HIV-1), and various small-molecule CCR5 antagonists are being developed to treat HIV-1 infection. It has been reported that such CCR5 antagonists, including TAK-779, bind to a putative binding pocket formed by transmembrane domains (TMs) 1, 2, 3 and 7 of CCR5, indicating the importance of the conformational changes of the TMs during virus entry. In this report, using a single-round infection assay with human CCR5 and its substitution mutants, we demonstrated that a new CCR5 antagonist, TAK-220, shares the putative interacting amino acid residues Asn252 and Leu255 in TM6 with TAK-779 but also requires the distinct residues Gly163 and Ile198 in TMs 4 and 5, respectively, for its inhibitory effect. We suggested that, together with molecular models of the interactions between the drugs and CCR5, the inhibitory activity of TAK-220 could involve direct interactions with amino acid residues in TMs 4, 5, and 6 in addition to those in the previously postulated binding pocket. The possible interaction of drugs with additional regions of the CCR5 molecule would help to develop a new small-molecule CCR5 antagonist.
G蛋白偶联受体CCR5是嗜巨噬细胞性1型人类免疫缺陷病毒(HIV-1)的主要共受体,目前正在研发各种小分子CCR5拮抗剂来治疗HIV-1感染。据报道,包括TAK-779在内的此类CCR5拮抗剂可与CCR5跨膜结构域(TM)1、2、3和7形成的假定结合口袋结合,这表明病毒进入过程中TM构象变化的重要性。在本报告中,我们使用人类CCR5及其替代突变体进行单轮感染试验,证明新型CCR5拮抗剂TAK-220与TAK-779在TM6中共有假定的相互作用氨基酸残基Asn252和Leu255,但还分别需要TM4和TM5中的不同残基Gly163和Ile198来发挥其抑制作用。我们认为,结合药物与CCR5之间相互作用的分子模型,TAK-220的抑制活性除了与先前假定的结合口袋中的氨基酸残基直接相互作用外,还可能涉及与TM4、TM5和TM6中的氨基酸残基直接相互作用。药物与CCR5分子其他区域可能的相互作用将有助于开发新型小分子CCR5拮抗剂。