Huang Chao, Jin Yang, Fu Panpan, Hu Kongying, Wang Mengxue, Zai Wenjing, Hua Ting, Song Xinluo, Ye Jianyu, Zhang Yiqing, Luo Gan, Wang Haiyu, Liu Jiangxia, Chen Jieliang, Li Xuwen, Yuan Zhenghong
Key Laboratory of Medical Molecular Virology (MOE/NHC), Research Unit of Cure of Chronic Hepatitis B Virus Infection (CAMS), Shanghai Frontiers Science Center of Pathogenic Microbes and Infection, School of Basic Medical Sciences, Shanghai Medical College Fudan University, Shanghai 200032, China.
State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Acta Pharm Sin B. 2024 Nov;14(11):4914-4933. doi: 10.1016/j.apsb.2024.07.019. Epub 2024 Aug 3.
Due to the limitations of current anti-HBV therapies, the HBV core (HBc or HBcAg) protein assembly modulators (CpAMs) are believed to be potential anti-HBV agents. Therefore, discovering safe and efficient CpAMs is of great value. In this study, we established a HiBiT-based high-throughput screening system targeting HBc and screened novel CpAMs from an in-house marine chemicals library. A novel lead compound , a derivative of the marine natural product naamidine J, has been successfully screened for potential anti-HBV activity. Bioactivity-driven synthesis was then conducted, and the structure‒activity relationship was analyzed, resulting in the discovery of the most effective compound (IC = 0.24 μmol/L). Furthermore, was found to significantly inhibit HBV replication in multiple cell models and exhibit a synergistic effect with tenofovir disoproxil fumarate (TDF) and IFNa2 for anti-HBV activity. Treatment with in a hydrodynamic-injection mouse model demonstrated significant anti-HBV activity without apparent hepatotoxicity. These findings suggest that the naamidine J derivative could be used as the HBV core protein assembly modulator to develop safe and effective anti-HBV therapies.
由于目前抗乙肝病毒疗法的局限性，乙肝病毒核心（HBc或HBcAg）蛋白组装调节剂（CpAMs）被认为是潜在的抗乙肝病毒药物。因此，发现安全有效的CpAMs具有重要价值。在本研究中，我们建立了基于HiBiT的靶向HBc的高通量筛选系统，并从内部海洋化合物库中筛选新型CpAMs。一种新型先导化合物，即海洋天然产物那米定J的衍生物，已成功筛选出具有潜在抗乙肝病毒活性的物质。随后进行了生物活性导向合成，并分析了构效关系，从而发现了最有效的化合物（IC = 0.24 μmol/L）。此外，发现该化合物在多种细胞模型中显著抑制乙肝病毒复制，并与替诺福韦酯（TDF）和IFNa2在抗乙肝病毒活性方面表现出协同作用。在水动力注射小鼠模型中用该化合物治疗显示出显著的抗乙肝病毒活性且无明显肝毒性。这些发现表明，那米定J衍生物可作为乙肝病毒核心蛋白组装调节剂用于开发安全有效的抗乙肝病毒疗法。
