通过肠道感染的肠道病毒与 1 型糖尿病 (T1D) 的发展有关。肠道病毒长时间从粪便排出与胰岛自身免疫有关。此外，在新近发病的 T1D 患者的胰岛中检测到了肠道病毒蛋白和病毒 RNA，这表明它们可能在破坏 β 细胞中发挥作用。尽管如此，目前尚无批准的专门针对肠道病毒感染用于疾病干预的抗病毒药物。药物再利用可以发现现有药物的新临床用途，并可以加快药物发现。此前，抗癌药物维莫非尼（Vemurafenib）对多种肠道病毒表现出前所未有的抗病毒活性。在本研究中，我们评估了 Vemurafenib 及其类似物在预防感染或减少与 T1D 相关的肠道病毒复制方面的功效。我们在肠上皮细胞 (IEC) 和产生胰岛素的 β 细胞中测试了维莫非尼。此外，我们建立了感染人类干细胞来源的胰岛 (SC-islet) 的方案，并在该模型中使用了 Vemurafenib 及其类似物。我们的研究表明，Vemurafenib 在 IEC 和 β 细胞系中表现出强大的抗病毒特性。维莫非尼类似物也具有抗病毒作用。 SC-胰岛表达病毒受体 CAR 和 DAF，分别在胰岛素和胰高血糖素阳性细胞中表达最高。 SC 胰岛被 CVB 成功感染，并且 Vemurafenib 及其类似物的抗病毒活性在大多数 SC 胰岛批次中得到证实。总之，我们的观察结果表明，维莫非尼及其类似物值得进一步探索，作为治疗肠道病毒引起的疾病（包括 T1D）的潜在抗病毒药物。版权所有 © 2024。由 Elsevier B.V. 出版。

Enteroviruses, which infect via the gut, have been implicated in type 1 diabetes (T1D) development. Prolonged faecal shedding of enterovirus has been associated with islet autoimmunity. Additionally, enteroviral proteins and viral RNA have been detected in the pancreatic islets of individuals with recent-onset T1D, implicating their possible role in beta cell destruction. Despite this, no approved antiviral drugs currently exist that specifically target enterovirus infections for utilisation in disease interventions. Drug repurposing allows for the discovery of new clinical uses for existing drugs and can expedite drug discovery. Previously, the cancer drug Vemurafenib demonstrated unprecedented antiviral activity against several enteroviruses. In the present study, we assessed the efficacy of Vemurafenib and an analogue thereof in preventing infection or reducing the replication of enteroviruses associated with T1D. We tested Vemurafenib in intestinal epithelial cells (IECs) and insulin-producing beta cells. Additionally, we established a protocol for infecting human stem cell-derived islets (SC-islets) and used Vemurafenib and its analogue in this model. Our studies revealed that Vemurafenib exhibited strong antiviral properties in IECs and a beta cell line. The antiviral effect was also seen with the Vemurafenib analogue. SC-islets expressed the viral receptors CAR and DAF, with their highest expression in insulin- and glucagon-positive cells, respectively. SC-islets were successfully infected by CVBs and the antiviral activity of Vemurafenib and its analogue was confirmed in most SC-islet batches. In summary, our observations suggest that Vemurafenib and its analogue warrant further exploration as potential antiviral agents for the treatment of enterovirus-induced diseases, including T1D.Copyright © 2024. Published by Elsevier B.V.