Treatment of dengue virus (DENV) and other flavivirus infections is an unmet medical need. The highly conserved flaviviral NS5 RNA-dependent RNA polymerase (RdRp) is an attractive antiviral target that interacts with NS3 and viral RNA within the replication complex assembly. Biochemical and cell-based evidence indicate that targeting cavity B may lead to dual RdRp and NS5-NS3 interaction inhibitors. By ligand-based design around 1H-pyrido[2,1-b][1,3]benzothiazol-1-one (PBTZ) 1, we identified new potent and selective DENV inhibitors that exert dual inhibition of NS5 RdRp and NS3-NS5 interaction, likely through binding cavity B. Resistance studies with compound 4 generated sequence variants in the 3'-untranslated region of RNA while further biochemical experiments demonstrated its ability to block also RNA-NS5 interaction, required for correct RNA synthesis in cells. These findings shed light on the potential mechanism of action for this class of compounds, underlying how PBTZs are very promising lead candidates for further evaluation.

中文翻译：

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吡咯并苯并噻唑酮通过抑制NS5聚合酶的多种功能发挥有效的抗登革热活性。

登革病毒（DENV）和其他黄病毒感染的治疗是尚未满足的医疗需求。高度保守的黄病毒NS5 RNA依赖型RNA聚合酶（RdRp）是有吸引力的抗病毒靶标，可与NS3和复制复合体内的病毒RNA相互作用。生化和基于细胞的证据表明，靶向腔B可能导致双重RdRp和NS5-NS3相互作用抑制剂。通过围绕1H-吡啶并[2,1-b] [1,3]苯并噻唑-1-酮（PBTZ）1的基于配体的设计，我们确定了新的有效和选择性DENV抑制剂，它们对NS5 RdRp和NS3-NS5都有双重抑制作用化合物4的抗性研究在RNA的3'-非翻译区域产生了序列变异，而进一步的生化实验表明，它也具有阻断RNA-NS5相互作用的能力，细胞中正确RNA合成所需的蛋白质。这些发现揭示了这类化合物的潜在作用机理，揭示了PBTZ如何成为非常有希望的进一步评估的潜在先导。