肌肽Carnosine抗乙型肝炎病毒的作用及机制研究

The current available agents for the treatment of hepatitis B virus (HBV) mainly include nucleotide analogues and interferon, which could effectively inhibit the virus, improve liver function, but cannot completely eliminate the virus, and easy to cause the virus mutation and viral breakthrough, and a variety of side effects. As an endogenous soluble peptide, carnosine exerts significant biological effects. Our previous study show that carnosine couldsuppress the synthesis of HBV DNA and expression of HBsAg in HBV cell model, suggesting that carnosine has the inhibitory effect on HBV. However, the regulation effects and mechanisms of carnosine on HBV are not clear. Based on the demand of new anti-HBV drugs, this study tends to explore the anti-HBV effects of carnosine in in vitro model of HBV cells and in vivo model of HBV transgenic mice. The TLR-NF-κB pathway, proteasome and heat stress protein activity of host cells are further analyzed. In addition, the antiviral and synergistic effects between carnosine and lamivudine are also elucidated. Collectively, this study will provide a new design platform for the anti-HBV drugs, and a novel research frontier for studying the function of carnosine.

目前治疗乙型病毒性肝炎的药物主要有两类：核苷酸类似物和干扰素，两者可以较好地抑制病毒、改善肝功能，但不能彻底清除病毒，且易导致病毒变异而引发病毒突破，及多种副作用。Carnosine作为内源水溶性二肽，具有显著生物学效应。前期工作显示：在HBV细胞模型中Carnosine能显著抑制HBV DNA和HBsAg表达，提示Carnosine对HBV有抑制作用，然而其具体调控作用及相关机理不详。基于抗HBV新靶点药物的需求，本课题拟在HBV细胞模型和转基因鼠两种水平研究Carnosine抗HBV效应，并对TLR-NF-κB通路，宿主细胞蛋白酶体或热应激蛋白活性进行深入探讨，分析Carnosine抗HBV可能作用机制。同时，对比Carnosine与拉米夫定抗病毒作用，研究二者的协同效果。本研究将为抗乙肝病毒新靶点药物研发，提供一种新的路径和候选靶标，并为Carnosine功能研究提供新的研究方向。

目前，全球有2.4亿人是慢性乙型肝炎感染者，虽然临床上有有效的预防性疫苗和有效的抗病毒治疗药物，但是并无治愈乙肝的药物存在。治疗性药物主要是核苷酸类似物和干扰素，两者可以较好地抑制病毒、改善肝功能，但不能彻底清除病毒，且易导致病毒变异而引发病毒突破，及多种副作用。Carnosine作为内源水溶性二肽，具有显著抑制肝损伤，抗氧化、清除自由基等生物学效应。亦有报道提示Carnosine具有抗病毒活性，所以，本项目主要研究该水溶性二肽的抗乙肝病毒活性及其相关作用机理。通过研究发现，Carnosine能够有效的抑制体外乙肝模型细胞的病毒DNA和病毒表面抗原的表达和分泌，该抑制效果是通过激活NF-κB相关通路，进而促进促炎细胞因子的分泌，从而达到抗病毒的作用。再者，在体内乙肝动物模型中发现，Carnosine能够剂量依赖性的抑制HBV病毒DNA的分泌，但其抑制效果弱于现有临床使用药物。乙肝的治疗需要多种策略联合用药，因此，本课题结合Carnosine的毒性弱和免疫激活特性，采用藕联Carnosine与核苷类似物药物，从而开发具有双重作用效果的抗HBV药物，为今后HBV的创新药物开发提供了新的思路。