流感病毒神经氨酸酶（NA）的结构、靶向药物设计与耐药机制研究

Influenza virus is an important cause of acute respiratory disease and results in significant morbidity and mortality throughout the world. The spread of 2009 pandemic H1N1 influenza viruses and infection of highly pathogenic avian influenza H5N1 virus have raised great concern about influenza prevention and control. Competitive inhibitors of neuraminidase (NA) have so far been demonstrated to be the most effective strategy against the unpredictability and high virulence of influenza, and their design has long been renowned as a classic example of structure-based drug design. However, the rapid emergence and global transmission of drug-resistant influenza viruses remain a great concern. Consequently, the development of new effective drugs is critical for the treatment and prevention of emerging highly pathogenic influenza strains...This project focuses on the structures and targeting inhibitors of influenza NA. Specifically, the characterization of variant NA structures, the biochemical and structural basis of NA enzymatic function, the molecular mechanism of NA drug resistance as well as the evaluation of novel inhibitors at both protein and virus level. Our comprehensive study of these key questions would provide considerable novel insight into the design and development of next generation anti-influenza drugs.

流感的频发性与致病性严重危害人类健康，干扰了人民的正常生活和社会稳定。尤其是2009 甲型H1N1 流感引发的大流行，造成了全世界范围的巨大恐慌。鉴于流感疫苗研发的限制性，以流感病毒神经氨酸酶（NA）为靶点设计的抑制剂是目前抵抗流感病毒最有效的策略。但是流感抑制剂的广泛使用导致耐药毒株频繁出现,使现有药物的使用面临瓶颈，新型可替代药物的设计研发至关重要。本项目拟通过结构生物学及分子病毒学的手段，进一步研究NA 酶促反应的结构与生化机制，探索突变株耐药的分子基础，从蛋白和病毒水平评估多种新型抑制剂的作用机制及应用前景。为设计与开发新一代抗流感药物提供充分的理论基础，缓解以耐药问题为主的现有神经氨酸酶抑制剂的诸多不足。

流感的频发性与致病性严重危害人类健康，干扰了人民的正常生活和社会稳定。尤其是2009 甲型H1N1 流感引发的大流行，造成了全世界范围的巨大恐慌。鉴于流感疫苗研发的限制性，以流感病毒神经氨酸酶（NA）为靶点设计的抑制剂是目前抵抗流感病毒最有效的策略。但是流感抑制剂的广泛使用导致耐药毒株频繁出现，使现有药物的使用面临瓶颈，新型可替代药物的设计研发至关重要。.本项目从不同流感病毒神经氨酸酶NA的结构特征、耐药机制，以及新型抗流感药物的设计、筛选与评估等方面开展研究，顺利完成了研究任务。首次解析了A型流感病毒亚型N3和N7的NA晶体结构，揭示了H7N9、H10N8和N2亚型的NA耐药机制，研究了NA抑制剂MS-257对于带有耐药突变的N2亚型神经氨酸酶的作用机制，阐明了多价抑制剂和组别特异性抑制剂的作用机制，开展了靶向多种亚型流感病毒NA的保护性抗体研发。发表SCI论文9篇，获得发明专利1项。