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.

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De Novo乙型肝炎病毒细胞进入的大环肽抑制剂

乙型肝炎病毒（HBV）构成了重大的公共卫生负担，当前可用的治疗方法通常无法治愈，因此需要开发新的治疗方法。在这里，我们应用了随机非标准肽整合发现（RaPID）筛选，以鉴定靶向HBV细胞表面受体牛磺胆酸钠共转运多肽（NTCP）的HBV进入的小大环肽抑制剂。这些分子除了具有抗HBV活性外，还抑制相关D型肝炎病毒（HDV）进入细胞，并且对各种HBV株具有活性（包括临床相关的对核苷酸（t）ide类似物具有抗药性和疫苗逃逸株）。 。重要的是，与其他结合NTCP的HBV进入抑制剂相比，这些大环肽