Bi Wenwen, Zhu Tao, Xu Yawen, Li Jianmin
Laboratory of Advanced Biotechnology, ZJU-Hangzhou Global Scientific and Technological Innovation Center, Zhejiang University, Hangzhou 311215, China.
Laboratory of Advanced Biotechnology, Beijing Institute of Biotechnology, Beijing 100071, China.
Int J Mol Sci. 2025 Jun 15;26(12):5729. doi: 10.3390/ijms26125729.
The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants with enhanced transmissibility and immune evasion underscores the urgent need for broad-spectrum antiviral therapeutics. In this study, we strategically engineered a novel dual-targeting peptide inhibitor, R1L25HR2, by conjugating the receptor-binding domain (RBD)-targeting peptide R1 with the heptad repeat 1 (HR1)-targeting peptide HR2 through an optimized 25-mer flexible linker (GGGGS)5, aiming to simultaneously block viral attachment and membrane fusion. R1L25HR2 potently and broadly inhibits the infection of SARS-CoV-2 and its emerging variants, including recent circulating strains JN.1 and KP.2, with IC values ranging from 5.3 to 253.5 nM, which is significantly more effective than HR2 and R1 alone. Mechanistically, R1L25HR2 inhibits viral attachment and membrane fusion by binding to both RBD and HR1 with low nanomolar affinity. These results highlight the innovative strategy of dual-targeting the RBD and HR1 domains as an effective approach to overcome viral resistance and achieve broad-spectrum antiviral activity.
具有增强传播性和免疫逃逸能力的严重急性呼吸综合征冠状病毒2（SARS-CoV-2）变体的出现凸显了对广谱抗病毒疗法的迫切需求。在本研究中，我们通过一个优化的25聚体柔性接头（GGGGS）5将靶向受体结合域（RBD）的肽R1与靶向七肽重复序列1（HR1）的肽HR2偶联，精心设计了一种新型双靶点肽抑制剂R1L25HR2，旨在同时阻断病毒附着和膜融合。R1L25HR2有效且广泛地抑制SARS-CoV-2及其新出现变体的感染，包括近期流行的毒株JN.1和KP.2，其半数抑制浓度（IC）值在5.3至253.5 nM之间，显著比单独的HR2和R1更有效。从机制上讲，R1L25HR2通过以低纳摩尔亲和力结合RBD和HR1来抑制病毒附着和膜融合。这些结果突出了双靶点靶向RBD和HR1结构域这一创新策略，作为克服病毒抗性并实现广谱抗病毒活性的有效方法。
