Antiviral drug design based on structural insights into the N-terminal domain and C-terminal domain of the SARS-CoV-2 nucleocapsid protein

基于新冠病毒核衣壳蛋白N端和C端结构域结构的抗病毒药物设计

Nucleocapsid(N) protein plays crucial roles in the life cycle of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2), including the formation of ribonucleoprotein(RNP) complex with the viral RNA.Here we reported the crystal structures of the N-terminal domain(NTD) and C-terminal domain(CTD) of the N protein and an NTD-RNA complex. Our structures reveal a unique tetramer organization of NTD and identify a distinct RNA binding mode in the NTD-RNA complex, which could contribute to the formation of the RNP complex. We also screened small molecule inhibitors of N-NTD and N-CTD and discovered that ceftriaxone sodium, an antibiotic, can block the binding of RNA to NTD and inhibit the formation of the RNP complex. These results together could facilitate the further research of antiviral drug design targeting N protein.

新型冠状病毒(SARS-CoV-2)的核衣壳蛋白在其生命周期中起着至关重要的作用,包括与病毒RNA形成核糖核蛋白复合体(RNP).本研究报告了核衣壳蛋白的N端结构域(NTD)和C端结构域(CTD)以及N端结构域-RNA复合物(NTD-RNA)的晶体结构,揭示了NTD独特的四聚体结构,并提出了NTD-RNA复合物中不同的RNA结合模式,这可能有助于RNP的形成.本研究还筛选到了同时是核衣壳蛋白NTD和CTD的小分子抑制剂头孢曲松钠,它可以通过阻断RNA与NTD的结合,抑制RNP的形成,从而阻断SARSCoV-2病毒的生活周期.这些结果有助于后续进一步开展以核衣壳蛋白为靶点的抗病毒药物设计研究.