2017年初爆发的H7N9禽流感及在患者体内分离的两株耐达菲毒株，对研发新型抗流感药物与流感及时监控提出了迫切要求。针对流感耐药株与神经氨酸酶（NA）抑制剂结合力降低进而体现出的耐药性，本项目以上市药物扎那米韦为母体，综合三种有效提高与NA结合力的改造策略，设计了一系列多价氟取代膦酸基扎那米韦衍生物，用以提高与耐药株NA的结合，解决毒株耐药性。对筛选出的抗流感活性最优的化合物，使用多种化学生物学手段对耐药机制及NA的结合进行分子机理研究，期望在寻找高活性神经氨酸酶抑制剂的同时，为理性设计抗流感药物提供实验依据。更进一步，将合成的与流感病毒具有高亲和力的化合物与微阵列芯片、表面等离子体共振、金纳米棒技术相结合，发展基于小分子的流感病毒尤其是耐药毒株的快速检测体系，改善原有基于抗原抗体相互作用的试剂盒的稳定性差、灵敏度低的缺点，指导临床合理用药。

Disease burden due to influenza is significant especially new pandemic H7N9 avian Flu in January 2017. Recently two Tamiflu resistant strains were isolated which make it an urgent need not only to develop new structure antiviral drugs but also monitor the surveillance. In this proposal, three effective structure modifications which can enhance the antiviral activity were combined together into Zanamivir backbone to get a serial of multivalent fluorinated zanamivir phosphonate analogs. Chemical biology technologies were used to further study the binding between neuramidinase on the virion and the analogs on molecular, protein, cell and animal level which can give the basic principles for the rational design of neuramidinase inhibitor and set up a platform for the evaluation of the antiviral compounds. Furthermore, the synthetic Zanamivir analogs which have high binding affinity to the influenza virus were attached on the microarray, surface plasmon resonance and nanorod sensor surface to develop rapid point of care diagnostics for all influenza strains especially for the drug resistance strains. This small molecule based technologies were expected to overcome the limitations of antigen detection assays and will guide clinical drug use.