JC polyomavirus (JCPyV) is a common human pathogen that results in a chronic asymptomatic infection in healthy adults. Under conditions of immunosuppression, JCPyV spreads to the central nervous system and can cause the fatal demyelinating disease progressive multifocal leukoencephalopathy (PML), a disease for which there are no vaccines or antiviral therapies. Retro‐2 is a previously identified small molecule inhibitor that was originally shown to block retrograde transport of toxins such as ricin toxin from endosomes to the Golgi apparatus and endoplasmic reticulum (ER), and Retro‐2.1 is a chemical analog of Retro‐2 that has been shown to inhibit ricin intoxication of cells at low nanomolar concentrations. Retro‐2 has previously been shown to prevent retrograde transport of JCPyV virions to the ER, but the effect of Retro‐2.1 on JCPyV infectivity is unknown. Here it is shown that Retro‐2.1 inhibits JCPyV with an EC₅₀ of 3.9 μM. This molecule inhibits JCPyV infection at dosages that are not toxic to human tissue culture cells. Retro‐2.1 was also tested against two other polyomaviruses, the human BK polyomavirus and simian virus 40, and was also shown to inhibit infection at similar concentrations. Viral uncoating studies demonstrate that Retro‐2.1 inhibits BKPyV infectivity in a manner similar to Retro‐2. These studies demonstrate that improved analogs of Retro‐2 can inhibit infection at lower dosages than Retro‐2 and further optimization of these compounds may lead to effective treatment options for those suffering from JCPyV infection and PML.

中文翻译：

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逆行运输抑制剂Retro-2.1抑制JC多瘤病毒感染性。

JC多瘤病毒（JCPyV）是一种常见的人类病原体，可在健康成年人中导致慢性无症状感染。在免疫抑制条件下，JCPyV传播至中枢神经系统，并可能导致致命的脱髓鞘疾病进行性多灶性白质脑病（PML），该疾病尚无疫苗或抗病毒疗法。Retro-2是一种先前鉴定的小分子抑制剂，最初被证明可阻止毒素（例如蓖麻毒素）从内体向高尔基体和内质网（ER）逆行转运，Retro-2.1是Retro-2的化学类似物，已显示在低纳摩尔浓度下抑制蓖麻毒蛋白中毒。以前已证明Retro-2可以阻止JCPyV病毒粒子逆向转运至ER，但是Retro-2的作用。关于JCPyV的传染性未知。此处显示Retro-2.1通过EC抑制JCPyV₅₀个3.9μM。该分子以对人组织培养细胞无毒的剂量抑制JCPyV感染。Retro-2.1还针对其他两种多瘤病毒（人类BK多瘤病毒和猿猴病毒40）进行了测试，并显示出在相似浓度下也能抑制感染。病毒脱壳研究表明，Retro-2.1以类似于Retro-2的方式抑制BKPyV的感染性。这些研究表明，改进的Retro-2的类似物可以以比Retro-2更低的剂量抑制感染，进一步优化这些化合物可能为患有JCPyV感染和PML的患者提供有效的治疗选择。