Discovery of Quinoline Analogues as Potent Antivirals against Enterovirus D68 (EV-D68).
Discovery of Quinoline Analogues as Potent Antivirals against Enterovirus D68 (EV-D68).
复制标题
DOI：
10.1021/acs.jmedchem.9b00115
复制
发表时间：
2019-04-25
影响因子：
7.3
通讯作者：
Wang J
中科院分区：
文献类型：
--
作者：
Musharrafieh R;Zhang J;Tuohy P;Kitamura N;Bellampalli SS;Hu Y;Khanna R;Wang J
肠道病毒D68（EV-D68）是一种非典型非脊髓灰质炎肠道病毒，主要感染人类呼吸系统，导致中度至重度呼吸道疾病。在极少数情况下，EV-D68 可以扩散到中枢神经系统并导致感染患者瘫痪，尤其是幼儿和免疫功能低下的个体。目前尚无批准的疫苗或抗病毒药物可用于预防和治疗 EV-D68。在本研究中，我们旨在通过构效关系研究来提高先前报道的 EV-D68 抑制剂地布卡因的抗病毒效力和选择性。总共合成了 60 种化合物，并使用病毒细胞病变效应 (CPE) 检测针对 EV-D68 进行了测试。与地布卡因相比，三种化合物 10a、12a 和 12c 被确定对五种不同的 EV-D68 病毒株具有显着提高的效力 (EC50 < 1 μM) 和高选择性指数 (SI > 180)。这些化合物还在 A172 和 SH-SY5Y 细胞等神经元细胞中表现出有效的抗病毒活性，表明它们可能被进一步开发用于治疗呼吸道感染和神经元感染。
Enterovirus D68 (EV-D68) is an atypical non-polio enterovirus that mainly infected the respiratory system of humans, leading to moderate to severe respiratory diseases. In rare cases, EV-D68 can spread to the central nervous system and causes paralysis in infected patients, especially young children and immunocompromised individuals. There is currently no approved vaccine or antiviral available for the prevention and treatment of EV-D68. In this study, we aimed to improve the antiviral potency and selectivity of a previously reported EV-D68 inhibitor, dibucaine, through structure-activity relationship studies. In total, sixty compounds were synthesized and tested against EV-D68 using the viral cytopathic effect (CPE) assay. Three compounds 10a, 12a, and 12c were identified to have significantly improved potency (EC50 < 1 μM) and a high selectivity index (SI > 180) compared to dibucaine against five different strains of EV-D68 viruses. These compounds also showed potent antiviral activity in neuronal cells such as A172 and SH-SY5Y cells, suggesting they might be further developed for the treatment of both respiratory infection as well as neuronal infection.
登录
查看更多内容
影响因子：
33.9
作者：
Abedi, Glen R.;Watson, John T.;Gerber, Susan I.
通讯作者：
Gerber, Susan I.
影响因子：
7.3
作者：
Wang Y;Hu Y;Xu S;Zhang Y;Musharrafieh R;Hau RK;Ma C;Wang J
通讯作者：
Wang J
影响因子：
4.9
作者：
Ulferts, Rachel;van der Linden, Lonneke;van Kuppeveld, Frank J. M.
通讯作者：
van Kuppeveld, Frank J. M.
影响因子：
7.4
作者：
François-Moutal L;Wang Y;Moutal A;Cottier KE;Melemedjian OK;Yang X;Wang Y;Ju W;Largent-Milnes TM;Khanna M;Vanderah TW;Khanna R
通讯作者：
Khanna R
影响因子：
7.6
作者：
Smee, Donald F.;Evans, W. Joseph;Nicolaou, K. C.;Tarbet, E. Bart;Day, Craig W.
通讯作者：
Day, Craig W.