多位点结合型苄基四氢异喹啉类流感病毒PA-Nter抑制剂的构效关系及作用机制研究

目前流感频繁爆发严重威胁人类生命健康，而现有抗流感药物品种少且易诱导耐药，因而开发具有新作用机制的抗流感病毒药物已迫在眉睫。流感病毒核酸内切酶PA-Nter是病毒在宿主细胞内完成转录及复制过程的关键蛋白，以其为靶点的PAN抑制剂已成为当前抗流感药物研发的热点。我们在前期研究中，以天然PAN抑制剂氢溴酸劳丹素为先导化合物，利用多位点结合策略对其进行结构改造，获得了新系列的具有3-羧基-1-苄基四氢异喹啉为结构特征的多位点结合型PAN抑制剂。其中，苄基四氢异喹啉衍生物LDS-3是潜在的首个四位点结合型PAN抑制剂，其在体内外对多个流感病毒株均具有较强的抑制作用。以此为基础，本项目拟运用基于结构的药物设计方法，在抗病毒活性指导下开展化学结构多样性的生物碱化合物库的构建及活性筛选，获得该类PAN抑制剂的构效关系并明确其作用机制，为新型、高效的多位点结合型PAN抑制剂类抗流感药物的研发提供科学依据。

Influenza virus (IFV) due to its frequency and pathogenicity has become a serious threat to human health in the near future. However, viral resistance to existing several inhibitors persists as major challenges to currently approved therapies. Thus, there is an urgent need for the development of new drugs with novel mechanism of action to prevent and treat influenza infection. The N-terminal domain of the PA (PAN) endonuclease is responsible for cap- snatching reaction to catalyze the transcription step, indicating PAN endonuclease inhibitors are hot antiviral therapies. It was found that D,L-laudanosoline was a natural influenza virus PAN endonuclease inhibitor, which was chosen as the lead compound. In our previous study, a new series of benzyl 1,2,3,4-tetrahydroisoquinoline derivatives were obtained as novel “three-sites binding”-typed or “four-sites binding”-typed PA-Nter inhibitors based on “multiple-sites binding” principle. Biological evaluations demonstrated that LDS-3 is a first potential “four-sites binding”-typed PAN endonuclease inhibitor, which showed strong anti-IFVs activity in vitro and vivo. Based on these above result, this project will construct the alkaloid library including structurally diverse tetrahydropapaverine derivatives via the structure-based drug design strategy in combination with antiviral activity screening. Then we will also focus on analysis of structure-activity relationships (SARs) and elucidation of the underlying mechanism of action or this kind of PAN endonuclease inhibitors structurally related to benzyl 1,2,3,4- tetrahydropapaverine derivatives. Our study will provide the scientific basis for the development of the novel and efficient “multiple-sites binding”-typed PAN endonuclease inhibitors as the new anti-IFVs drugs.