Laboratory of Molecular Medicine and Neuroscience, National Institute of Neurological Disorders and Stroke/NIH, 10 Center Drive, Bethesda, MD 20892-1296, USA.
Antimicrob Agents Chemother. 2010 Nov;54(11):4723-32. doi: 10.1128/AAC.00837-10. Epub 2010 Sep 7.
JC virus (JCV) is a polyomavirus that infects human oligodendrocytes, leading to development of progressive multifocal leukoencephalopathy (PML), an often fatal demyelinating disease occurring in immunocompromised individuals. Currently there are no effective therapies for the treatment of PML that result in clearance of JCV from the brain. Cidofovir (CDV) is an acyclic nucleoside phosphonate that inhibits DNA polymerases and has been used for the treatment of PML. However, CDV demonstrated little efficacy as a treatment for PML and causes substantial side effects to patients. To improve efficacy and reduce the toxicity of CDV, a lipid-ester derivative, CMX001, was generated by Chimerix and is currently in multicenter phase II clinical trials for the prevention or control of cytomegalovirus infection in hematopoietic stem cell transplant recipients and of BK virus in the urine of stem cell or renal allograft recipients. CMX001 caused minimal cytotoxic effects in human fetal brain SVG cells when used at concentrations between 0.01 μM and 0.1 μM. CMX001 resulted in a dose-dependent decrease in the number of JCV-infected cells during initial infection and nearly eliminated JCV-infected cells during an established infection. In addition, CMX001 treatment resulted in a 60% reduction in JCV DNA copy number during initial infection, which suggests that suppression of JCV infection by CMX001 is likely due to inhibition of virus DNA replication. This study demonstrates that CMX001 suppresses JCV infection at concentrations that have limited toxicity to human brain cells, indicating its potential use to limit JCV replication in infected patients.
JC 病毒（JCV）是一种感染人类少突胶质细胞的多瘤病毒，导致进行性多灶性脑白质病（PML）的发展，这是一种经常发生在免疫功能低下个体中的致命脱髓鞘疾病。目前，尚无有效的治疗方法可以清除大脑中的 JCV。更昔洛韦（CDV）是一种无环核苷磷酸酯，可抑制 DNA 聚合酶，已用于治疗 PML。然而，CDV 作为 PML 的治疗方法效果甚微，并且对患者造成严重的副作用。为了提高疗效并降低 CDV 的毒性，Chimerix 公司生成了一种脂质酯衍生物 CMX001，目前正在进行多中心 II 期临床试验，用于预防或控制造血干细胞移植受者中的巨细胞病毒感染和干细胞或肾移植受者尿液中的 BK 病毒。CMX001 在 0.01 μM 和 0.1 μM 之间的浓度时，对人胎脑 SVG 细胞的细胞毒性作用最小。CMX001 导致初始感染时 JCV 感染细胞数量呈剂量依赖性减少，并且在已建立的感染中几乎消除了 JCV 感染细胞。此外，CMX001 治疗导致初始感染时 JCV DNA 拷贝数减少 60％，这表明 CMX001 通过抑制病毒 DNA 复制来抑制 JCV 感染。这项研究表明，CMX001 以对人脑细胞毒性有限的浓度抑制 JCV 感染，表明其在抑制感染患者 JCV 复制方面具有潜在用途。
