Department of Virology, Oswaldo Cruz Foundation (Fiocruz), Avenida Professor Moraes Rego, Recife, Pernambuco, Brazil.
Department of Veterinary Medicine, Federal University of Viçosa (UFV), Av. PH Rolfs, s/n, Viçosa, Minas Gerais 36570-900, Brazil.
Int J Antimicrob Agents. 2017 Dec;50(6):718-725. doi: 10.1016/j.ijantimicag.2017.08.016. Epub 2017 Aug 10.
Since the emergence of Zika virus (ZIKV) in Brazil in 2015, 48 countries and territories in the Americas have confirmed autochthonous cases of disease caused by the virus. ZIKV-associated neurological manifestations and congenital defects make the development of safe and effective antivirals against ZIKV of utmost importance. Here we evaluated the antiviral activity of 6-methylmercaptopurine riboside (6MMPr), a thiopurine nucleoside analogue derived from the prodrug azathioprine, against the epidemic ZIKV strain circulating in Brazil. In all of the assays, an epithelial (Vero) and a human neuronal (SH-SY5Y) cell line were used to evaluate the cytotoxicity and effective concentrations of 6MMPr against ZIKV. Levels of ZIKV-RNA, viral infectious titre and the percentage of infected cells in the presence or absence of 6MMPr were used to determine antiviral efficacy. 6MMPr decreased ZIKV production by >99% in both cell lines in a dose- and time-dependent manner. Interestingly, 6MMPr was 1.6 times less toxic to SH-SY5Y cells compared with Vero cells, presenting a 50% cytotoxic concentrations (CC) of 460.3 µM and 291 µM, respectively. The selectivity index of 6MMPr for Vero and SH-SY5Y cells was 11.9 and 22.7, respectively, highlighting the safety profile of the drug to neuronal cells. Taken together, these results identify, for the first time, the thiopurine nucleoside analogue 6MMPr as a promising antiviral candidate against ZIKV that warrants further in vivo evaluation.
自 2015 年巴西出现寨卡病毒（ZIKV）以来，美洲 48 个国家和地区已确认发生了由该病毒引起的本地病例。寨卡病毒相关的神经表现和先天性缺陷使得开发针对寨卡病毒的安全有效的抗病毒药物变得至关重要。在这里，我们评估了 6-甲基巯基嘌呤核糖核苷（6MMPr）的抗病毒活性，6MMPr 是一种来自前药硫唑嘌呤的硫代嘌呤核苷类似物，针对在巴西流行的寨卡病毒株。在所有的试验中，我们使用上皮（Vero）和人神经（SH-SY5Y）细胞系来评估 6MMPr 对寨卡病毒的细胞毒性和有效浓度。使用 ZIKV-RNA 水平、病毒感染滴度和存在或不存在 6MMPr 时的感染细胞百分比来确定抗病毒功效。6MMPr 以剂量和时间依赖的方式使两种细胞系中的 ZIKV 产量降低了>99%。有趣的是，6MMPr 对 SH-SY5Y 细胞的毒性比 Vero 细胞低 1.6 倍，分别呈现出 50%细胞毒性浓度（CC）为 460.3µM 和 291µM。6MMPr 对 Vero 和 SH-SY5Y 细胞的选择性指数分别为 11.9 和 22.7，突出了该药物对神经元细胞的安全性。综上所述，这些结果首次确定了硫代嘌呤核苷类似物 6MMPr 是一种有前途的抗寨卡病毒候选药物，值得进一步进行体内评估。
