Department of Chemistry, Graduate School of Science, The University of Tokyo, Tokyo 113-0033, Japan.
Department of Virology II, National Institute of Infectious Diseases, Tokyo 162-8640, Japan; Department of Applied Biological Sciences, Tokyo University of Science, Noda 278-8510, Japan; JST CREST, Saitama 332-0012, Japan.
Cell Chem Biol. 2018 Jul 19;25(7):906-915.e5. doi: 10.1016/j.chembiol.2018.04.011. Epub 2018 May 17.
Hepatitis B virus (HBV) constitutes a significant public health burden, and currently available treatment options are not generally curative, necessitating the development of new therapeutics. Here we have applied random non-standard peptide integrated discovery (RaPID) screening to identify small macrocyclic peptide inhibitors of HBV entry that target the cell-surface receptor for HBV, sodium taurocholate cotransporting polypeptide (NTCP). In addition to their anti-HBV activity, these molecules also inhibit cellular entry by the related hepatitis D virus (HDV), and are active against diverse strains of HBV (including clinically relevant nucleos(t)ide analog-resistant and vaccine escaping strains). Importantly, these macrocyclic peptides, in contrast to other NTCP-binding HBV entry inhibitors, exhibited no inhibition of NTCP-mediated bile acid uptake, making them appealing candidates for therapeutic development.
乙型肝炎病毒（HBV）对公共健康构成了重大威胁，而目前可用的治疗方法通常无法根治，因此需要开发新的治疗方法。在这里，我们应用随机非标准肽综合发现（RaPID）筛选来鉴定针对 HBV 细胞表面受体——牛磺胆酸钠共转运多肽（NTCP）的小分子大环肽抑制剂。除了具有抗 HBV 活性外，这些分子还能抑制相关的丁型肝炎病毒（HDV）的细胞进入，对多种 HBV 株（包括临床相关的核苷（酸）类似物耐药和疫苗逃逸株）均有活性。重要的是，与其他 NTCP 结合的 HBV 进入抑制剂相比，这些大环肽对 NTCP 介导的胆汁酸摄取没有抑制作用，这使它们成为治疗开发的有吸引力的候选药物。
