新型抗乙肝病毒哒嗪酮类小分子的优化及降解相关蛋白小分子探针的发现

Hepatitis B virus may lead to life-long infection, live damage, cirrhosis and liver cancer. So far, the approved chemotherapeutic anti-HBV agents in clinical application are nucleoside analogues. However, emergence of drug-resistance and relapse are frequent after long-term therapy with all the nucleoside analogues beside tenofovir.Thus, new non-nucleos(t)ide agents targeting different stages in the viral life cycle are not only expected against wild-type and nucleos(t)ide inhibitors-resistant viruses but also aim to achieve functional treatment of HBV infection. In the high-throughput screening of our in-house collection of compounds for anti-HBV activity, novel pyridazinone was identified as a modestly potent HBV inhibitor with the primary SARs. The lead compunds targeting nucleocapsid function with potent antiviral activity, low cytotoxicity, sensitivity to nucleoside-analog resistant HBV mutants and synergistic effect with nucleoside-analogs in HepG2.2.15 cell. Unfortunally, the lead compound was unstable in liver with low exposure in mouse. Base on the previous SARs, this project will continue to explore the further structure-activity relationship (SAR) and structure-property relationship (SPR) for the discovery of the novel anti-HBV drug candidate. In addition, we firstly designed the small hybrid molecules by linking a ligand for ubiqutin ligase that maybe degradate of the HBV core protein. Hopefully, this project will provide the new sight to lead to virus eradication and functional cure of HBV ultimately.

乙型肝炎病毒感染可引起肝癌、肝纤维化、肝功能不全等疾病，是我国严峻的公共卫生问题。目前治疗药物为核苷类化合物，易产生抗性和发生耐药变异，并且终生服药。因此，以HBV生命周期中其它过程为靶点的新型非核苷类药物研究，不仅是对核苷类药物耐药的需求，也是探索解决乙肝病人终身服药的关键科学问题。本课题合成的化合物库通过高通量筛选发现新型的活性化合物，通过构效关系研究，得到体外活性优、且毒性低的先导化合物，并确定了该类化合物的部分关键药效团，其机制研究表明作用于HBV核壳体的组装，对核苷类药物耐药的HBV突变株仍保持很强的抑制作用，但体内肝脏的靶向性差。本项目以前期化合物的构效关系研究为基础，以提高化合物活性及成药性为目的，进行先导化合物的结构优化，为新型的抗HBV候选化合物的发现奠定基础。同时，该申请项目首次提出链接泛素化官能团的设计理念，以期降解核壳体蛋白，探索清除HBV病毒避免反弹的可行性。

本项目以前期活性化合物的构效关系研究为基础，以提高化合物活性及成药性为目的，进行先导化合物的结构优化，获得多个体外高活性化合物。通过前药策略对高活性化合物进行成药性优化，得到氨基酸酯前药化合物。对前药进行AAV-HBV小鼠模型上体内药效学考察、代谢性质评价，获得了体内外活性高、代谢性质良好、结构新颖的酞嗪酮类抗乙肝病毒候选化合物。完成了候选化合物工艺、质量研究、代谢性质及初步毒理实验等一系列临床前研究。该类候选化合物可能的作用机制是诱导HBV组装空的核心颗粒；在腺相关病毒（AAV）介导的HBV慢性感染性小鼠动物模型上，灌胃给予该类候选化合物7周后并停药后，小鼠血清中HBV DNA水平，血清HBsAg和HBeAg水平能持续显著降低；病理解剖表明，小鼠肝脏中HBcAg细胞显著减少，小鼠肝脏中cccDNA水平降低。该类候选化合物为功能性治愈乙肝的联合或单用一线药物研发奠定了基础。

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