Discovery of novel small molecules targeting hepatitis B virus core protein from marine natural products with HiBiT-based high-throughput screening

IF 14.7 1区医学 Q1 PHARMACOLOGY & PHARMACY

Acta Pharmaceutica Sinica. B Pub Date : 2024-08-03 DOI:10.1016/j.apsb.2024.07.019

Chao Huang, Yang Jin, Panpan Fu, Kongying Hu, Mengxue Wang, Wenjing Zai, Ting Hua, Xinluo Song, Jianyu Ye, Yiqing Zhang, Gan Luo, Haiyu wang, Jiangxia Liu, Jieliang Chen, Xuwen Li, Zhenghong Yuan

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引用次数: 0

Abstract

Due to the limitations of current anti-HBV therapies, the HBV core (HBc) 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.

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利用基于 HiBiT 的高通量筛选，从海洋天然产物中发现靶向乙型肝炎病毒核心蛋白的新型小分子化合物

由于目前抗 HBV 疗法的局限性，HBV 核心（HBc）蛋白组装调节剂（CpAMs）被认为是潜在的抗 HBV 药物。因此，发现安全高效的 CpAMs 具有重要价值。在这项研究中，我们建立了一个基于 HiBiT 的高通量筛选系统，以 HBc 为目标，从内部海洋化学物质库中筛选新型 CpAMs。我们成功地筛选出了一种新型先导化合物，它是海洋天然产物呐脒 J 的衍生物，具有潜在的抗 HBV 活性。然后进行了生物活性驱动合成，并分析了结构-活性关系，最终发现了最有效的化合物（IC = 0.24 μmol/L）。此外，还发现该化合物能在多种细胞模型中明显抑制 HBV 复制，并与富马酸替诺福韦二吡呋酯（TDF）和 IFNa2 在抗 HBV 活性方面具有协同作用。在水动力注射小鼠模型中的治疗显示了显著的抗 HBV 活性，且无明显肝毒性。这些发现表明，naamidine J 衍生物可用作 HBV 核心蛋白组装调节剂，以开发安全有效的抗 HBV 疗法。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Acta Pharmaceutica Sinica. B Pharmacology, Toxicology and Pharmaceutics-General Pharmacology, Toxicology and Pharmaceutics

CiteScore

22.40

自引率

5.50%

发文量

1051

审稿时长

19 weeks

期刊介绍： The Journal of the Institute of Materia Medica, Chinese Academy of Medical Sciences, and the Chinese Pharmaceutical Association oversees the peer review process for Acta Pharmaceutica Sinica. B (APSB). Published monthly in English, APSB is dedicated to disseminating significant original research articles, rapid communications, and high-quality reviews that highlight recent advances across various pharmaceutical sciences domains. These encompass pharmacology, pharmaceutics, medicinal chemistry, natural products, pharmacognosy, pharmaceutical analysis, and pharmacokinetics. A part of the Acta Pharmaceutica Sinica series, established in 1953 and indexed in prominent databases like Chemical Abstracts, Index Medicus, SciFinder Scholar, Biological Abstracts, International Pharmaceutical Abstracts, Cambridge Scientific Abstracts, and Current Bibliography on Science and Technology, APSB is sponsored by the Institute of Materia Medica, Chinese Academy of Medical Sciences, and the Chinese Pharmaceutical Association. Its production and hosting are facilitated by Elsevier B.V. This collaborative effort ensures APSB's commitment to delivering valuable contributions to the pharmaceutical sciences community.