NTCP-S267F突变对HBV-preS1多态性的影响及其在优化HBV病毒入胞抑制剂的作用研究

以病毒受体蛋白NTCP为靶点的入胞抑制剂有望用于消除HBV和HDV感染。基于HBV-preS1结构域合成的衍生肽可阻断HBV和HDV进入肝细胞；但亚洲人常见的NTCP-S267F突变，能明显降低现有HBV-preS1衍生肽与NTCP的结合。申请人前期研究发现：抵抗HBV感染的NTCP-S267F纯合突变患者仍存在慢性HBV感染；且携带NTCP-S267F突变慢乙肝患者的HBV-preS1结构域存在多个突变（如S17A、P32L和G35R等）。在此基础上，申请人依托研究团队的大样本临床队列和数据，提出基于NTCP-S267F突变遗传背景下HBV-preS1的多态性，优化HBV病毒入胞抑制剂的策略，综合采用二代测序、计算机辅助药物设计和分子生物学实验（细胞实验和SPR实验）相结合的方法优化HBV-preS1衍生肽入胞抑制剂，为满足HBV和HDV的精准治疗提供理论依据。

Virus entry inhibitors targeting sodium taurocholate co-transporting polypeptide (NTCP) are expected to be useful in eliminating HBV and HDV infections. Peptides derived from the consensus sequence of HBV-preS1 domain can effectively inhibit the entry of HBV and HDV into hepatocytes. However, the common NTCP-S267F mutation in the Asian population significantly reduces the binding between the clinical trial drug Myrcludex B and NTCP. The applicant’s previous study found that HBV replicates in one NTCP-S267F homozygous patient who theoretically resists HBV infection. Several mutations such as S17A, P32L, and G35R are found in the HBV-preS1 domain in patients with NTCP-S267F mutation. On this basis, the applicant proposes to optimize HBV-preS1-derived virus entry inhibitor based on HBV-preS1 variability induced by NTCP-S267F mutation. The combination of next-generation sequencing, computer-aided drug design, and various molecular biology experiments are used to optimize HBV-preS1-derived peptides. The study provides optimal strategies for the precise treatment of HBV and HDV patients with NTCP-S267F mutation host genetic background.