冠状病毒S蛋白S2亚单位中广谱抗冠状病毒药物靶点的研究

冠状病毒的高变异特性成为研发高效广谱抗冠状病毒药物和抗体的主要障碍。我们分析了新冠病毒表面刺突（S）蛋白上氨基酸的序列，发现位于S2亚单位中的三个功能区 ─ FP、HR1、HR2的氨基酸序列最为保守。它们为了避免或减少免疫系统的攻击，基本上保持在隐蔽的状态，只是在病毒与宿主细胞膜发生融合的一瞬间暴露在一个狭小的空间, 而全长的IgG抗体（150Kd）无法进入该空间与之结合，因此这三个功能区不能成为IgG抗体的作用靶点。但由于其不易产生免疫逃避和耐药突变，可能是小分子纳米抗体（15Kd）、多肽及化合物的干预靶点。我们将从纳米抗体、多肽及化合物库中筛选与这些功能区结合，并具有广谱抗冠状病毒作用的抑制剂，作为探针来寻找其中的干预靶点。同时，将采用一系列的先进技术来分析作用于这些靶点的广谱抗冠状病毒抑制剂的作用机制，为今后研发高效广谱的抗冠状病毒药物和中和抗体奠定理论和实验基础。

The high mutation property of coronaviruses is a major obstacle to the development of highly effective and broad-spectrum anti-coronavirus drugs and antibodies. We have analyzed the sequence of amino acids on the spike (S) protein of coronaviruses and found that the amino acid sequences of the three functional regions in S2 subunit - FP, HR1, and HR2 were the most conservative. To avoid immune system's attack by, these functional regions are generally hidden, only at the moment when the viral membrane starts to fuse with the host cell membrane, they transiently expose to a small space, to which the full-length IgG antibody (150Kd) cannot access. Therefore, these three functional regions cannot be the target of the IgG antibody, thus not being susceptible to immune escape and drug-resistance mutations. However, they may be the targets of nanobodies (15Kd), peptides and compounds. We will screen from their libraries for the nanobodies, peptides, and compounds that bind to these functional regions and have a broad-spectrum anti-coronavirus activities. We will use them as probes to find the intervention targets. At the same time, we will use a series of advanced technologies to investigate the mechanism of action of these broad-spectrum anti-coronavirus inhibitors acting on these targets, and lay a theoretical and experimental foundation for the future development of high-efficient and broad-spectrum anti-coronavirus drugs and neutralizing antibodies.