流感病毒血凝素共价抑制剂的设计、合成及活性研究

Design,synthesis,and biological evaluation of covalent inhibitors targeting influenza virus hemagglutinin

近年来流感频发,针对传统靶点抗流感药物(如扎那米韦和奥司他韦)的耐药病毒大量出现,迫切需求开发新靶点、新作用机制的抗流感药物。本研究针对流感病毒血凝素(HA)底物结合位点附近的赖氨酸(Lys133和Lys222),设计了系列具有共价结合潜力的唾液酸类化合物(1a–1h)。活性研究表明该系列化合物对两种流感病毒HA蛋白的结合力较母体化合物唾液酸(SA)有明显提升,其中化合物1d与阳性化合物2,6-唾液酸乳糖胺(2,6-SLN)持平(KD=38.2和39.6μM);该系列化合物安全无毒(对MDCK细胞CC50>1 mM),其中化合物1d可有效抑制流感病毒在MDCK细胞中的复制。本研究提出了基于流感病毒HA的共价抑制新策略,深入发掘有望获得新型强效HA抑制剂。

The ongoing evolution of influenza strains and the limited effectiveness of existing anti-influenza drugs underscore the imperative for novel therapeutics.In addressing this,we developed and synthesized several sialic acid(SA)analogs,designed as potential covalent inhibitors by targeting lysine residues(Lys133 and Lys222)proximal to the substrate binding site of hemagglutinin(HA).The affinities of these compounds for HA were meticulously assessed using surface plasmon resonance(SPR).Intriguingly,all target compounds exhibited superior affinities for HA compared to the parent compound SA.Notably,compound 1d demonstrated a binding potency similar to that of the positive control(2,6-SLN),with KD values of 38.2μM and 39.6μM,respectively.Importantly,all compounds demonstrated non-cytotoxicity to MDCK cells,and compound 1d displayed robust inhibitory effects on the influenza virus in vitro.The development of covalent inhibitors targeting HA,as outlined in this study,presented a rational and promising strategy for the creation of potent HA inhibitors.