神经氨酸酶作为冠心病治疗新靶标及其抑制剂老药新用的研究

神经氨酸酶是一类识别糖蛋白和糖脂末端糖苷键的水解酶，在促进病毒释放和维持细胞结构功能中发挥重要作用。课题组前期基于临床大样本和功能代谢组学手段，发现神经氨酸酶在缺血心肌组织中高表达，是心肌损伤的标志物，而抑制神经氨酸酶可发挥心肌保护作用。鉴于此，本项目提出假说：神经氨酸酶是冠心病治疗的新靶标，神经氨酸酶抑制剂药物（奥司他韦和扎那米韦，用于抗流感病毒）具有治疗冠心病的新用途。拟将采用病人样本、多种细胞动物模型、心肌特异性基因敲除/敲入小鼠，研究神经氨酸酶在冠心病发生发展中的特殊作用，确证神经氨酸酶是冠心病可干预新靶标；证实神经氨酸酶抑制剂药物治疗冠心病的新用途；阐明神经氨酸酶入核及调控TLR4/Sirt7信号通路参与心肌缺血损伤的分子机制；解析人源神经氨酸酶的蛋白晶体结构，以此为靶点开展创新药物设计。研究成果将为心血管疾病提供新的可干预靶点，为神经氨酸酶抑制剂“老药新用”拓展新领域。

Neuraminidases are glycoside hydrolase enzymes that catalyze the removal of sialic acid (N-acetylneuraminic acid) moieties from glycoproteins and glycolipids. Neuraminidases play an important role in promoting spread of influenza virus and maintaining cells structure and function. Based on large-scale clinical biological samples, the applicant’s group observed that neuraminidase-1 is significantly elevated in ischemic myocardial tissue by functional metabolomics, suggesting that neuraminidase-1 is a potential biomarker for coronary heart disease (CHD). It was also observed that inhibiting the activities of neuraminidases protects cardiomyocytes and the heart from myocardial injury (Circulation, 2018; J Am Coll Cardiol, 2016). Based on these previous results, this project proposes a hypothesis that neuraminidase is a new target for the treatment of CHD, and the neuraminidase inhibitors, named oseltamivir and zanamivir that are two widely used anti-influenza drugs, can be used to protect myocardium from ischemic injury. The research contents include: (1) Patient samples, several cellular and animal models, and myocardial tissue-specific knockout/knock-in mice models will be employed to explore the biological functions of neuraminidase in progression of CHD. Multiple techniques will be used to confirm neuraminidase as a novel intervention target for CHD. (2) The new use of oseltamivir and zanamivir for treatment of CHD will be validated by in vitro and in vivo experiments. (3) The mechanism by which neuraminidase translocates into the nuclei and then induces myocardial injury partly by targeting TLR4/Sirt7 signalling pathways will be elucidated through omics and molecular biology techniques. (4) The crystal structure of human neuraminidase will be determined using x-ray technology, and the new drugs will be designed based on the structure of neuraminidase. This research will provide a new intervention target for cardiovascular diseases, and expand new use for the neuraminidase inhibitors.