<br>针对 HBV 衣壳蛋白的抗 HBV 药物的开发,RSC Medicinal Chemistry

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针对 HBV 衣壳蛋白的抗 HBV 药物的开发
RSC Medicinal Chemistry ( IF 4.1 ) Pub Date : 2023-08-24 , DOI: 10.1039/d3md00258f
Takuya Kobayakawa ₁ , Masayuki Amano _{2,

3} , Miyuki Nakayama ₁ , Kohei Tsuji ₁ , Takahiro Ishii ₁ , Yutaro Miura ₁ , Kouki Shinohara ₁ , Kenichi Yamamoto ₁ , Masao Matsuoka ₃ , Hirokazu Tamamura ₁

Affiliation

乙型肝炎是一种病毒性肝炎，是由乙型肝炎病毒（HBV）感染引起的。这种疾病会发展为慢性肝炎、肝硬化和肝癌。为了治疗乙型肝炎，必须排除病毒和肝细胞核中形成的共价闭合环状DNA (cccDNA)。乙型肝炎衣壳蛋白 (HBc) 是一种不可或缺的蛋白质，它形成包裹病毒 DNA 的衣壳。由于 HBc 与 cccDNA 的转录调控相关，因此该蛋白将成为彻底治愈乙型肝炎的有吸引力的靶标。通过对化合物库进行计算机筛选，发现了一种小化合物 Cpd4 ( 1 )，它与疏水空腔结合位于 HBc 蛋白四聚体界面的内袋中，已被鉴定。在抗 HBV 检测中，这种合成化合物 Cpd4 ( 1 ) 降低了与 HBV 增殖相关的 HBV 核心相关抗原 (HBcrAg) 的量，并降低了 HBV 表面抗原 (HBsAg) 的量，即与 cccDNA 的量相关。以Cpd4( 1 )为先导化合物，设计合成了20种1的衍生物，并考察了它们的构效关系。因此，每种化合物与靶蛋白氨基酸残基之间的特异性相互作用似乎并不重要，但可以与疏水空腔结合的化合物的形状/大小可能在高抗乙型肝炎病毒活性的表达中很重要，并且发现了更有效的衍生物 TKB-HBV-CA-001 ( 3b )。这些结果将有助于开发新型抗乙型肝炎药物以彻底治愈乙型肝炎。

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Development of anti-HBV agents targeting HBV capsid proteins

Hepatitis B is a viral hepatitis, which is caused by infection of hepatitis B virus (HBV). This disease progresses to chronic hepatitis, cirrhosis and liver cancer. To treat hepatitis B, exclusion of virus and covalently closed circular DNA (cccDNA) that is formed in hepatocyte nucleus is necessary. A hepatitis B capsid protein (HBc) is an indispensable protein, which forms the capsid that encapsulates viral DNA. Since HBc is correlated to the transcriptional regulation of cccDNA, this protein would be an attractive target for complete cure of hepatitis B. By in silico screening of a library of compounds, a small compound, Cpd4 (1), which binds to a hydrophobic cavity located in the inner pocket on the tetramer interface of HBc proteins, was identified. In anti-HBV assays, this synthetic compound, Cpd4 (1) decreased the amount of HBV core related antigen (HBcrAg), which has been correlated with the proliferation of HBV, and decreased the amount of HBV surface antigen (HBsAg), which is correlated with the amount of cccDNA. Based on Cpd4 (1) as a lead compound, 20 derivatives of 1 were designed and synthesized and their structure–activity relationships were examined. As a result, specific interactions between each compound and amino acid residues of the target protein appeared to be unimportant but the shape/size of compounds which can bind to the hydrophobic cavity might be important in the expression of high anti-HBV activity, and a more potent derivative, TKB-HBV-CA-001 (3b), was discovered. These results will be useful in the development of novel anti-HBV agents for a complete cure of hepatitis B.

更新日期：2023-08-24

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