Department of Medicine, Division of Infectious Diseases and Geographic Medicine, and Department of Microbiology and Immunology , Stanford University School of Medicine , Stanford , California 94305 , United States.
Medicinal Chemistry, Rega Institute for Medical Research , KU Leuven , Herestraat 49, Bus 1041 , 3000 Leuven , Belgium.
J Med Chem. 2018 Jul 26;61(14):6178-6192. doi: 10.1021/acs.jmedchem.8b00613. Epub 2018 Jul 16.
There is an urgent need for strategies to combat dengue and other emerging viral infections. We reported that cyclin G-associated kinase (GAK), a cellular regulator of the clathrin-associated host adaptor proteins AP-1 and AP-2, regulates intracellular trafficking of multiple unrelated RNA viruses during early and late stages of the viral lifecycle. We also reported the discovery of potent, selective GAK inhibitors based on an isothiazolo[4,3- b]pyridine scaffold, albeit with moderate antiviral activity. Here, we describe our efforts leading to the discovery of novel isothiazolo[4,3- b]pyridines that maintain high GAK affinity and selectivity. These compounds demonstrate improved in vitro activity against dengue virus, including in human primary dendritic cells, and efficacy against the unrelated Ebola and chikungunya viruses. Moreover, inhibition of GAK activity was validated as an important mechanism of antiviral action of these compounds. These findings demonstrate the potential utility of a GAK-targeted broad-spectrum approach for combating currently untreatable emerging viral infections.
迫切需要针对登革热和其他新发病毒感染的策略。我们曾报道过，细胞周期蛋白 G 相关激酶（GAK）是网格蛋白相关宿主衔接蛋白 AP-1 和 AP-2 的细胞调节剂，可调节多种无相关性 RNA 病毒在病毒生命周期的早期和晚期阶段的细胞内运输。我们还曾报道过，基于异噻唑并[4,3-b]吡啶支架发现了有效的、选择性的 GAK 抑制剂，尽管其抗病毒活性中等。在此，我们描述了发现新型异噻唑并[4,3-b]吡啶的努力，这些化合物保持了对 GAK 的高亲和力和选择性。这些化合物在体外对登革热病毒（包括对人原代树突状细胞）的活性得到了改善，对无关的埃博拉病毒和基孔肯雅热病毒也具有疗效。此外，抑制 GAK 活性已被验证为这些化合物抗病毒作用的重要机制。这些发现表明，针对 GAK 的广谱方法在治疗目前无法治疗的新发病毒感染方面具有潜在的应用价值。
