University of Ljubljana, Faculty of Pharmacy, Aškerčeva 7, 1000 Ljubljana, Slovenia.
Rega Institute, KU Leuven, Herestraat 49, 3000 Leuven, Belgium.
Bioorg Chem. 2020 May;98:103733. doi: 10.1016/j.bioorg.2020.103733. Epub 2020 Mar 8.
Seasonal or pandemic influenza virus infections are a worldwide health problem requiring antiviral therapy. Since virus resistance to the established neuraminidase inhibitors and novel polymerase inhibitors is growing, new drug targets are needed. Heat shock protein 90 (Hsp90) is associated with several aspects of the influenza virus life cycle, and is considered a relevant host cell target. We report here on a series of benzo[d]thiazole and 4,5,6,7-tetrahydrobenzo[d]thiazole derivatives with robust and selective activities against influenza A (H1N1, H3N2) and influenza B viruses. Two compounds, 1 and 4, have low micromolar EC values and show high binding affinities for Hsp90, which suggests that inhibition of Hsp90 is the mechanism underlying their antiviral effects. These compounds represent suitable scaffolds for designing novel Hsp90 inhibitors with favourable activities against influenza virus.
季节性或大流行性流感病毒感染是一个全球性的健康问题，需要抗病毒治疗。由于病毒对已确立的神经氨酸酶抑制剂和新型聚合酶抑制剂的耐药性不断增加，因此需要新的药物靶点。热休克蛋白 90（Hsp90）与流感病毒生命周期的几个方面有关，被认为是相关的宿主细胞靶标。我们在此报告了一系列苯并[d]噻唑和 4,5,6,7-四氢苯并[d]噻唑衍生物，它们对甲型（H1N1、H3N2）和乙型流感病毒具有强大而选择性的活性。两种化合物 1 和 4 的 EC 值均低至微摩尔，对 Hsp90 具有高结合亲和力，这表明抑制 Hsp90 是其抗病毒作用的机制。这些化合物代表了设计具有抗流感病毒活性的新型 Hsp90 抑制剂的合适支架。
