新型靶向HBV衣壳蛋白抑制剂的设计、合成及活性研究

Hepatitis B is a serious infectious disease caused by the hepatitis B virus (HBV), which severely affect the human's health. HBV capsid protein inhibitors can inhibit virus replication and block hepatocyte infection, which reduce and eventually clear HBV. Although the existing capsid protein inhibitors possess desired anti-drug resistance, they suffer from high toxicity and poor pharmacokinetic properties. In this project, based on our previous study and the complex crystal structure of the capsid protein with ligand, novel HBV capsid protein assembly inhibitors are designed by precisely introducing moiety with multi-site binding to the tolerant region and diverse groups pointing to the solvent-exposed region of capsid protein. Then the target compounds will be obtained through the construction of a virtual combinatorial library followed by multi-level virtual screening. Afterwards, 3D-QSAR will be established after synthesis and biological evaluation of the desired compounds. What’s more, further structural modification and optimization will be carried out based on molecular docking and molecular dynamics simulation. Hopefully, after several rounds of screening, promising lead compounds with improved efficacy and good pharmacokinetics will be identified, which may provide valuable information for the anti-HBV drug research and promote to achieve the goal of WHO to eliminate the viral hepatitis by 2030.

乙肝是由乙肝病毒引起的重大传染性疾病，严重威胁公众健康。HBV衣壳蛋白抑制剂具有抑制病毒的复制和阻断肝细胞感染的双重作用，从而减少并最终清除乙肝病毒。现有的衣壳蛋白抑制剂虽然具有良好的抗耐药性，但存在毒性大和药代动力学性质差的缺点。本课题基于我们前期研究基础以及衣壳蛋白晶体复合物结构生物学研究，采用在衣壳蛋白可容纳区“多位点结合”的精准药物设计和衣壳蛋白溶剂开口区结构多样性修饰策略，通过虚拟组合库的构建、多层级虚拟筛选获得结构新颖的目标化合物；再通过化合物定向合成和生物活性评价等环节建立三维定量构效关系，基于分子对接和分子动力学模拟对化合物进一步结构修饰和优化。经过多次结构优化、活性筛选和初步成药性评价，期望找到高效低毒和良好药代动力学性质的先导化合物，为研究开发成药性显著的新型乙肝病毒候选药物奠定基础，对世界卫生组织提出的2030年消除肝炎危害的目标具有重要意义。

乙肝是由乙肝病毒引起的重大传染性疾病，严重威胁公众健康。HBV衣壳蛋白抑制剂具有抑制病毒的复制和阻断肝细胞感染的双重作用，从而减少并最终清除乙肝病毒。现有的衣壳蛋白抑制剂虽然具有良好的抗耐药性，但存在毒性大和药代动力学性质差的缺点。本课题基于前期的研究基础以及衣壳蛋白晶体复合物结构生物学研究，采用在衣壳蛋白可容纳区“多位点结合”的精准药物设计和衣壳蛋白溶剂开口区结构多样性修饰策略，设计并合成了四个系列，共183个目标化合物，大部分都表现了较好的抗HBV DNA复制活性。其中，化合物1n、2d、3s和3t在抗病毒或毒性方面都优于先导化合物NVR 3-778。除此之外，化合物3s和3t抗HBV DNA复制活性优于目前临床III期候选药物GLS4和临床一线药物恩替卡韦，有望成为成药性显著的新型乙肝病毒候选药物，对世界卫生组织提出的2030年消除肝炎危害的目标具有重要的意义。