ZOOVIR, Department of Biotechnology, Instituto Nacional de Investigación y Tecnología Agraria y Alimentaria (INIA), Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain.
Instituto de Quimica Medica (IQM), CSIC, Madrid, Spain.
Antimicrob Agents Chemother. 2023 Apr 18;67(4):e0168722. doi: 10.1128/aac.01687-22. Epub 2023 Mar 15.
The flavivirus life cycle is strictly dependent on cellular lipid metabolism. Polyphenols like gallic acid and its derivatives are promising lead compounds for new therapeutic agents as they can exert multiple pharmacological activities, including the alteration of lipid metabolism. The evaluation of our collection of polyphenols against West Nile virus (WNV), a representative medically relevant flavivirus, led to the identification of ,'-(dodecane-1,12-diyl)bis(3,4,5-trihydroxybenzamide) and its 2,3,4-trihydroxybenzamide regioisomer as selective antivirals with low cytotoxicity and high antiviral activity (half-maximal effective concentrations [ECs] of 2.2 and 0.24 μM, respectively, in Vero cells; ECs of 2.2 and 1.9 μM, respectively, in SH-SY5Y cells). These polyphenols also inhibited the multiplication of other flaviviruses, namely, Usutu, dengue, and Zika viruses, exhibiting lower antiviral or negligible antiviral activity against other RNA viruses. The mechanism underlying their antiviral activity against WNV involved the alteration of sphingolipid metabolism. These compounds inhibited ceramide desaturase (Des1), promoting the accumulation of dihydrosphingomyelin (dhSM), a minor component of cellular sphingolipids with important roles in membrane properties. The addition of exogenous dhSM or Des1 blockage by using the reference inhibitor GT-11 {-[(1,2)-2-hydroxy-1-hydroxymethyl-2-(2-tridecyl-1-cyclopropenyl)ethyl]octanamide} confirmed the involvement of this pathway in WNV infection. These results unveil the potential of novel antiviral strategies based on the modulation of the cellular levels of dhSM and Des1 activity for the control of flavivirus infection.
黄病毒的生命周期严格依赖于细胞脂质代谢。没食子酸及其衍生物等多酚类化合物是有前途的新型治疗药物先导化合物，因为它们具有多种药理活性，包括改变脂质代谢。我们对一系列多酚类化合物针对西尼罗河病毒（WNV）的评估，WNV 是一种具有医学相关性的代表性黄病毒，鉴定出了，'-(十二烷-1,12-二基)双(3,4,5-三羟基苯甲酰胺)及其 2,3,4-三羟基苯甲酰胺区域异构体，它们具有低细胞毒性和高抗病毒活性（在 Vero 细胞中的半最大有效浓度 [EC] 分别为 2.2 和 0.24 μM，在 SH-SY5Y 细胞中的 EC 分别为 2.2 和 1.9 μM）。这些多酚类化合物还抑制了其他黄病毒，即乌苏图病毒、登革热病毒和寨卡病毒的增殖，对其他 RNA 病毒表现出较低的抗病毒活性或可忽略不计的抗病毒活性。它们对 WNV 的抗病毒活性的作用机制涉及改变神经酰胺代谢。这些化合物抑制神经酰胺去饱和酶（Des1），促进二氢神经鞘氨醇（dhSM）的积累，dhSM 是细胞神经鞘脂中的一种次要成分，在膜特性中具有重要作用。添加外源性 dhSM 或使用参考抑制剂 GT-11（{-[(1,2)-2-羟基-1-羟甲基-2-(2-十三烷基-1-环丙基乙烯基)乙基]辛酰胺}）阻断 Des1，证实了该途径在 WNV 感染中的参与。这些结果揭示了基于调节 dhSM 和 Des1 活性的细胞水平的新型抗病毒策略的潜力，用于控制黄病毒感染。
