Novel low molecular weight spirodiketopiperazine derivatives potently inhibit R5 HIV-1 infection through their antagonistic effects on CCR5
Novel low molecular weight spirodiketopiperazine derivatives potently inhibit R5 HIV-1 infection through their antagonistic effects on CCR5
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DOI：
10.1074/jbc.m105670200
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发表时间：
2001-09-14
影响因子：
4.8
通讯作者：
Mitsuya, H
中科院分区：
文献类型：
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作者：
Maeda, K;Yoshimura, K;Mitsuya, H
鉴定了新的低分子量螺二酮哌嗪衍生物，其通过对CCR 5的拮抗作用而有效地抑制R5人类免疫缺陷病毒1型（HIV-1）感染。一种这样的化合物E913（M-r 484）特异性阻断巨噬细胞炎性蛋白-1 α（MIP-1 α）与CCR 5的结合（IC 50 0.002 μ M）和MIP-1 α引起的细胞Ca 2+动员（IC 50类似于0.02 μ M）。E913有效抑制实验室和原代R5 HIV-1毒株以及各种多药耐药嗜单核细胞/巨噬细胞（R5）HIV-1的复制，IC 50值为0.03至0.06 μ M。E913对T细胞嗜性（X4）HIV-1无活性;然而，当与CXCR 4拮抗剂AMD-3100联合使用时，E913有效且协同地抑制双嗜性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。E913被证明与识别CCR 5的第二胞外环（ECL 2B）的C-末端一半的抗体竞争结合CCR 5。E913及其类似物在啮齿动物中具有耐酸和口服生物利用度。这些数据保证了螺二酮哌嗪衍生物作为HIV-1感染的潜在治疗剂被进一步开发。
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-1 alpha (MIP-1 alpha) to CCR5 (IC50 0.002 muM) and MIP-1 alpha -elicited cellular Ca2+ mobilization (IC50 similar to 0.02 muM). 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 IC50 values of 0.03 to 0.06 muM. 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.