Guangzhou Institutes of Biomedicine and Heath, Chinese Academy of Sciences, 190 Kaiyuan Road, Guangzhou, 510530, PR China; University of Chinese Academy of Sciences, No. 19 Yuquan Road, Beijing, 100049, PR China.
Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education, Guangzhou, PR China; Guangdong Province Key Laboratory of Functional Molecules in Oceanic Microorganism (Sun Yat-sen University), Bureau of Education, Guangzhou, PR China; Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, PR China.
Antiviral Res. 2018 Jan;149:95-105. doi: 10.1016/j.antiviral.2017.11.005. Epub 2017 Nov 10.
Dengue fever, caused by four distinct serotypes of dengue virus (DENV-1 to -4), has become the fastest spreading human infectious disease in recent years. Despite extensive efforts, there is no specific antiviral treatment approved for dengue until now. Nucleoside inhibitors represent an actively pursued area to develop small-molecule anti-dengue virus agents. In this study, we designed and synthesized a series of 7-deazapurine nucleoside derivatives and evaluated their anti-DENV activity. Our design strategy and structure activity relationship studies revealed 6e as the most potent inhibitor (EC = 2.081 ± 1.102 μM) of DENV replication. 6e suppressed RNA levels and DENV E protein expression, without causing any apparent cytotoxicity in A549 and HepG2 cells (CC = 150.06 ± 11.42 μM, SI = 72.11 in A549 cells, and CC = 146.47 ± 11.05 μM and SI = 63.7 in HepG2 cells). In addition, 6e showed similar inhibition potency against four serotypes of DENV, suggesting that it restrains some evolutionarily conserved targets essential for DENV replication. We conceive that 6e may serve as a promising lead compound for anti-DENV drug development.
登革热是由四种不同血清型的登革病毒（DENV-1 至 DENV-4）引起的，已成为近年来传播速度最快的人类传染病。尽管进行了广泛的努力，但迄今为止，仍没有专门针对登革热的抗病毒治疗方法获得批准。核苷抑制剂是开发小分子抗登革热病毒药物的一个积极研究领域。在这项研究中，我们设计并合成了一系列 7-脱氮嘌呤核苷衍生物，并评估了它们的抗 DENV 活性。我们的设计策略和结构活性关系研究揭示了 6e 是最有效的 DENV 复制抑制剂（EC = 2.081 ± 1.102 μM）。6e 抑制 RNA 水平和 DENV E 蛋白表达，而在 A549 和 HepG2 细胞中没有引起明显的细胞毒性（CC = 150.06 ± 11.42 μM，SI = 72.11 在 A549 细胞中，CC = 146.47 ± 11.05 μM 和 SI = 63.7 在 HepG2 细胞中）。此外，6e 对四种血清型的 DENV 表现出相似的抑制作用，表明它抑制了一些对 DENV 复制至关重要的进化保守靶标。我们认为 6e 可能是一种有前途的抗 DENV 药物开发的先导化合物。
