Department of Chemistry and Technology of Drugs, University of Perugia , 06123 Perugia, Italy.
J Med Chem. 2013 Dec 27;56(24):10118-31. doi: 10.1021/jm401560v. Epub 2013 Dec 13.
The limited number of drug classes licensed for treatment of influenza virus (Flu), together with the continuous emergence of viral variants and drug resistant mutants, highlights the urgent need to find antivirals with novel mechanisms of action. In this context, the viral RNA-dependent RNA polymerase (RdRP) subunits assembly has emerged as an attractive target. Starting from a cycloheptathiophene-3-carboxamide derivative recently identified by us for its ability to disrupt the interaction between the PA and PB1 subunits of RdRP, we have designed and synthesized a series of analogues. Their biological evaluation led to the identification of more potent protein-protein interaction inhibitors, endowed with antiviral activity that also encompassed a number of clinical isolates of FluA, including an oseltamivir-resistant strain, and FluB, without showing appreciable toxicity. From this study, the cycloheptathiophene-3-carboxamide scaffold emerged as being particularly suitable to impart anti-Flu activity.
用于治疗流感病毒 (Flu) 的药物种类有限，加上病毒变异株和耐药突变株的不断出现，这突显了寻找具有新型作用机制的抗病毒药物的迫切需求。在这种情况下，病毒 RNA 依赖性 RNA 聚合酶 (RdRP) 亚基组装已成为一个有吸引力的靶标。从最近我们发现的一种环庚三噻吩-3-甲酰胺衍生物开始，该化合物因其能够破坏 RdRP 的 PA 和 PB1 亚基之间的相互作用而被识别，我们设计并合成了一系列类似物。对它们的生物学评估导致了更有效的蛋白质-蛋白质相互作用抑制剂的鉴定，这些抑制剂具有抗病毒活性，同时还包括多种临床分离的 FluA，包括奥司他韦耐药株和 FluB，而没有表现出明显的毒性。从这项研究中，环庚三噻吩-3-甲酰胺支架被证明特别适合赋予抗 Flu 活性。
