Zika virus (ZIKV) was identified in 1947 in the Zika forest of Uganda and it has emerged recently as a global health threat, with recurring outbreaks and its associations with congenital microcephaly through maternal fetal transmission and Guillain-Barré syndrome. Currently, there are no United States (US) Food and Drug Administration (FDA)-approved vaccines or antivirals to treat ZIKV infections, which underscores an urgent medical need for the development of disease intervention strategies to treat ZIKV infection and associated disease. Drug repurposing offers various advantages over developing an entirely new drug by significantly reducing the timeline and resources required to advance a candidate antiviral into the clinic. Screening the ReFRAME library, we identified ten compounds with antiviral activity against the prototypic mammarenavirus lymphocytic choriomeningitis virus (LCMV). Moreover, we showed the ability of these ten compounds to inhibit influenza A and B virus infections, supporting their broad-spectrum antiviral activity. In this study, we further evaluated the broad-spectrum antiviral activity of the ten identified compounds by testing their activity against ZIKV. Among the ten compounds, Azaribine (SI-MTT = 146.29), AVN-944 (SI-MTT = 278.16), and Brequinar (SI-MTT = 157.42) showed potent anti-ZIKV activity in post-treatment therapeutic conditions. We also observed potent anti-ZIKV activity for Mycophenolate mofetil (SI-MTT = 20.51), Mycophenolic acid (SI-MTT = 36.33), and AVN-944 (SI-MTT = 24.51) in pre-treatment prophylactic conditions and potent co-treatment inhibitory activity for Obatoclax (SI-MTT = 60.58), Azaribine (SI-MTT = 91.51), and Mycophenolate mofetil (SI-MTT = 73.26) in co-treatment conditions. Importantly, the inhibitory effect of these compounds was strain independent, as they similarly inhibited ZIKV strains from both African and Asian/American lineages. Our results support the broad-spectrum antiviral activity of these ten compounds and suggest their use for the development of antiviral treatment options of ZIKV infection.

中文翻译：

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ZIKV复制抑制剂的鉴定。

寨卡病毒（ZIKV）于1947年在乌干达的寨卡森林中发现，最近已成为一种全球性健康威胁，其反复发作和通过母体胎儿传播和吉兰-巴雷综合征与先天性小头畸形相关。当前，尚无美国食品药品管理局（FDA）批准的用于治疗ZIKV感染的疫苗或抗病毒药，这突显了迫切的医疗需求，需要开发治疗ZIKV感染和相关疾病的疾病干预策略。与重新开发药物相比，重新使用药物具有各种优势，因为它大大减少了将候选抗病毒药物推向临床所需的时间和资源。筛选ReFRAME库，我们鉴定了十种对原型乳腺肾炎淋巴细胞性脉络膜脑膜炎病毒（LCMV）具有抗病毒活性的化合物。此外，我们显示了这十种化合物抑制甲型和乙型流感病毒感染的能力，支持了它们的广谱抗病毒活性。在这项研究中，我们通过测试其对ZIKV的活性，进一步评估了十种已鉴定化合物的广谱抗病毒活性。在这十种化合物中，氮杂rib嗪（SI-MTT = 146.29），AVN-944（SI-MTT = 278.16）和Brequinar（SI-MTT = 157.42）在治疗后的治疗条件下显示出强大的抗ZIKV活性。我们还观察到了对霉酚酸酯（SI-MTT = 20.51），霉酚酸（SI-MTT = 36.33）和AVN-944（SI-MTT = 24）的有效抗ZIKV活性。51）在预处理预防条件下以及在联合治疗条件下对Obatoclax（SI-MTT = 60.58），氮杂多巴胺（SI-MTT = 91.51）和霉酚酸酯（SI-MTT = 73.26）的有效联合治疗抑制活性。重要的是，这些化合物的抑制作用与菌株无关，因为它们同样抑制了非洲和亚洲/美洲血统的ZIKV菌株。我们的结果支持了这十种化合物的广谱抗病毒活性，并表明它们可用于开发ZIKV感染的抗病毒治疗方案。