Maeda K, Yoshimura K, Shibayama S, Habashita H, Tada H, Sagawa K, Miyakawa T, Aoki M, Fukushima D, Mitsuya H
Department of Internal Medicine II, Kumamoto University School of Medicine, Kumamoto 860-0811, Japan.
J Biol Chem. 2001 Sep 14;276(37):35194-200. doi: 10.1074/jbc.M105670200. Epub 2001 Jul 13.
Novel low molecular weight spirodiketopiperazine derivatives which potently inhibit R5 human immunodeficiency virus type 1 (HIV-1) infection through their antagonistic effects on CCR5 were identified. One such compound E913 (M(r) 484) specifically blocked the binding of macrophage inflammatory protein-1alpha (MIP-1alpha) to CCR5 (IC(50) 0.002 microm) and MIP-1alpha-elicited cellular Ca(2+) mobilization (IC(50) approximately 0.02 microm). E913 potently inhibited the replication of laboratory and primary R5 HIV-1 strains as well as various multidrug-resistant monocyte/macrophage tropic (R5) HIV-1 at IC(50) values of 0.03 to 0.06 microm. E913 was inactive against T cell tropic (X4) HIV-1; however, when combined with a CXCR4 antagonist AMD-3100, E913 potently and synergistically inhibited the replication of dualtropic HIV-1 and a 50:50 mixture of R5 and X4 HIV-1. Antagonism in anti-HIV-1 activity was not seen when E913 was combined with the reverse transcriptase inhibitor zidovudine or protease inhibitors. E913 proved to compete with the binding of antibodies to CCR5 which recognize the C-terminal half of the second extracellular loop (ECL2B) of CCR5. E913 and its analogs are acid-resistant and orally bioavailable in rodents. These data warrant that spirodiketopiperazine derivatives be further developed as potential therapeutics for HIV-1 infection.
通过对CCR5的拮抗作用，鉴定出了新型低分子量螺二酮哌嗪衍生物，其能有效抑制R5型人类免疫缺陷病毒1型（HIV-1）感染。其中一种化合物E913（分子量484）特异性阻断巨噬细胞炎性蛋白-1α（MIP-1α）与CCR5的结合（半数抑制浓度[IC(50)]为0.002微摩尔）以及MIP-1α诱导的细胞钙动员（IC(50)约为0.02微摩尔）。E913能有效抑制实验室和原代R5 HIV-1毒株以及各种耐多药单核细胞/巨噬细胞嗜性（R5）HIV-1毒株的复制，IC(50)值为0.03至0.06微摩尔。E913对T细胞嗜性（X4）HIV-1无活性；然而，当与CXCR4拮抗剂AMD-3100联合使用时，E913能有效且协同抑制双嗜性HIV-1以及R5和X4 HIV-1的50:50混合物的复制。当E913与逆转录酶抑制剂齐多夫定或蛋白酶抑制剂联合使用时，未观察到抗HIV-1活性的拮抗作用。事实证明，E913能与识别CCR5第二个细胞外环（ECL2B）C端一半的抗体与CCR5的结合相互竞争。E913及其类似物耐酸，在啮齿动物中口服具有生物利用度。这些数据表明螺二酮哌嗪衍生物有必要作为HIV-1感染的潜在治疗药物进一步开发。
