Department of Biology, Faculty of Science, Chulalongkorn University, Bangkok, 10330, Thailand.
Graduate Program, Faculty of Medicine, Chulalongkorn University, Bangkok, 10330, Thailand.
Antiviral Res. 2018 Mar;151:27-38. doi: 10.1016/j.antiviral.2018.01.010. Epub 2018 Feb 3.
Dengue infection is a global burden affecting millions of world population. Previous studies indicated that flavanones were potential dengue virus inhibitors. We discovered that a novel flavanone derivative, 5-hydroxy-7-methoxy-6-methylflavanone (FN5Y), inhibited DENV2 pH-dependent fusion in cell-based system with strong binding efficiency to DENV envelope protein at K (P83, L107, K128, L198), K' (T48, E49, A50, L198, Q200, L277), X' (Y138, V354, I357), and Y' (V97, R99, N103, K246) by molecular dynamic simulation. FN5Y inhibited DENV2 infectivity with ECs (and selectivity index) of 15.99 ± 5.38 (>6.25), and 12.31 ± 1.64 (2.23) μM in LLC/MK2 and Vero cell lines, respectively, and inhibited DENV4 at 11.70 ± 6.04 (>8.55) μM. CC50s in LLC/MK2, HEK-293, and HepG2 cell lines at 72 h were higher than 100 μM. Time-of-addition study revealed that the maximal efficacy was achieved at early after infection corresponded with pH-dependent fusion. Inactivating the viral particle, interfering with cellular receptors, inhibiting viral protease, or the virus replication complex were not major targets of this compound. FN5Y could become a potent anti-flaviviral drug and can be structurally modified for higher potency using simulation to DENV envelope as a molecular target.
登革热感染是一种全球性负担，影响着全球数百万人。先前的研究表明，黄烷酮类化合物是潜在的登革热病毒抑制剂。我们发现一种新型黄烷酮衍生物，5-羟基-7-甲氧基-6-甲基黄烷酮（FN5Y），在基于细胞的系统中抑制 DENV2 pH 依赖性融合，与 DENV 包膜蛋白具有很强的结合效率，结合部位为 K（P83、L107、K128、L198）、K'（T48、E49、A50、L198、Q200、L277）、X'（Y138、V354、I357）和 Y'（V97、R99、N103、K246）。分子动力学模拟结果表明，FN5Y 抑制 DENV2 感染的 EC50（和选择性指数）分别为 15.99±5.38（>6.25）和 12.31±1.64（2.23）μM，在 LLC/MK2 和 Vero 细胞系中，分别抑制 DENV4 的 EC50 为 11.70±6.04（>8.55）μM。72 小时时，LLC/MK2、HEK-293 和 HepG2 细胞系中的 CC50 均高于 100μM。加药时间研究表明，最大疗效出现在感染后早期，与 pH 依赖性融合相对应。该化合物的主要作用靶点不是病毒粒子失活、干扰细胞受体、抑制病毒蛋白酶或病毒复制复合物。FN5Y 可能成为一种有效的抗黄病毒药物，并可通过模拟 DENV 包膜作为分子靶点进行结构修饰以提高其效力。
