Discovery and characterization of vicriviroc (SCH 417690), a CCR5 antagonist with potent activity against human immunodeficiency virus type 1
Discovery and characterization of vicriviroc (SCH 417690), a CCR5 antagonist with potent activity against human immunodeficiency virus type 1
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DOI：
10.1128/aac.49.12.4911-4919.2005
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发表时间：
2005-12-01
影响因子：
4.9
通讯作者：
Baroudy, BM
中科院分区：
文献类型：
--
作者：
Strizki, JM;Tremblay, C;Baroudy, BM
通过阻断宿主细胞辅助受体CCR 5和CXCR 4来抑制人类免疫缺陷病毒1型（HIV-1）感染是抗逆转录病毒治疗的新兴策略。目前，临床上正在开发几种新型辅助受体抑制剂，早期结果已被证明是有希望的。在这份报告中，我们描述了一种新的CCR 5拮抗剂，vicriviroc（以前的SCH-D或SCH 417690），具有改善的抗病毒活性和药代动力学特性相比，SCH-C，以前描述的CCR 5拮抗剂。与SCH-C一样，vicriviroc与CCR 5受体特异性结合，可防止嗜CCR 5的HIV-1分离株感染靶细胞。在抗病毒试验中，vicriviroc对遗传多样性和耐药性HIV-1分离株显示出强效、广谱活性，并且在抑制病毒复制方面始终比SCH-C更有效。该化合物与所有其他类别的获批抗逆转录病毒药物联合使用时表现出协同抗HIV活性。竞争结合测定显示，与SCH-C相比，vicriviroc以更高的亲和力与CCR 5结合。功能测定，包括钙通量、鸟苷5 '-[S-35]三磷酸交换和趋化性的抑制，证实了vicriviroc通过抑制趋化因子对CCR 5的信号传导而作为受体拮抗剂。最后，与SCH-C相比，vicriviroc对人ether a-go-go相关基因转录物离子通道的亲和力降低，表明心脏效应的可能性降低。Vicriviroc代表了治疗HIV-1感染的有希望的新候选药物。
Inhibiting human immunodeficiency virus type 1 (HIV-1) infection by blocking the host cell coreceptors CCR5 and CXCR4 is an emerging strategy for antiretroviral therapy. Currently, several novel coreceptor inhibitors are being developed in the clinic, and early results have proven promising. In this report, we describe a novel CCR5 antagonist, vicriviroc (formerly SCH-D or SCH 417690), with improved antiviral activity and pharmacokinetic properties compared to those of SCH-C, a previously described CCR5 antagonist. Like SCH-C, vicriviroc binds specifically to the CCR5 receptor and prevents infection of target cells by CCR5-tropic HIV-1 isolates. In antiviral assays, vicriviroc showed potent, broad-spectrum activity against genetically diverse and drug-resistant HIV-1 isolates and was consistently more active than SCH-C in inhibiting viral replication. This compound demonstrated synergistic anti-HIV activity in combination with drugs from all other classes of approved antiretrovirals. Competition binding assays revealed that vicriviroc binds with higher affinity to CCR5 than SCH-C. Functional assays, including inhibition of calcium flux, guanosine 5'-[S-35] triphosphate exchange, and chemotaxis, confirmed that vicriviroc acts as a receptor antagonist by inhibiting signaling of CCR5 by chemokines. Finally, vicriviroc demonstrated diminished affinity for the human ether a-go-go related gene transcript ion channel compared to SCH-C, suggesting a reduced potential for cardiac effects. Vicriviroc represents a promising new candidate for the treatment of HIV-1 infection.