高效广谱抗冠状病毒新型拟肽类抑制剂的功能及抗病毒机制的研究

Recently, continuously emerging highly pathogenic human coronaviruses (HCoVs) remain a significant threat to human health. However, no broad-spectrum anti-HCoVs drug is currently available for clinical use, thus it is desiderated to strengthen the development of effective and safe therapeutics against HCoVs infection. In our previous studies, we have identified a potent and broad-spectrum peptidomimetic inhibitor against multiple HCoVs infection with IC50 at low nanomolar level, which outcompetes the reported entry inhibitors. In this subject, we will use the pseudotyped- and live- HCoVs infection assays and various animal models to comprehensively evaluate its antiviral broad-spectrum, in vivo efficacy and in vivo drug-forming properties, providing theoretical guidance and experimental basis for its clinical application in future. More importantly, the previous results also show that the peptidomimetic inhibitor targets a novel target site, which has not been reported yet. Hence, we will combine molecular-biology and biochemical techniques to further explore the unique target and the precise antiviral mechanism of the peptidomimetic inhibitor, further expanding the human cognition of HCoVs infection. Therefore, this project will provide new clues and theoretical basis for the development of the potent and broad-spectrum anti-HCoVs drugs with our own intellectual property rights.

近年来，不断爆发的高致病性人冠状病毒（HCoVs）对人类的生存与健康造成巨大威胁，然而目前临床上尚未有有效治疗HCoVs感染的药物，因此亟需进一步加大药物研发力度。前期工作中，我们初步发现了一个可广谱高效抑制HCoVs感染的拟肽类抑制剂，其IC50在低纳摩尔水平，远高于已报道的入侵抑制剂。在本课题中，我们将利用多种假病毒感染模型和活病毒感染模型全面评估其抗HCoVs的广谱性，并在多种动物模型上评估该抑制剂的体内有效性及成药性，为其以后的临床应用提供理论指导和实验依据。更为重要的是，前期实验结果显示该拟肽类抑制剂作用于非传统的全新靶点，在本课题中我们将结合分子生物学、生物化学等技术进一步深入探索其作用靶点及抗病毒机制，进一步丰富人类对HCoVs感染过程的认知。因此，本课题的开展将为研发具有我国自主知识产权、可高效广谱抗HCoVs的新型药物提供重要线索和理论依据。

近年来，不断爆发的人冠状病毒对人类的生存与健康造成巨大威胁，因此，亟需进一步加大研发广谱抗病毒药物的力度。在本课题中，针对多种冠状病毒及其变异株，我们系统地建立假病毒感染模型，从而全面评估了XS007A等多肽或拟肽类小分子抑制剂有效性和广谱性。在HCoV-OC43的小鼠感染模型上，系统地证明了XS007A的体内抗病毒活性，为其以后的临床应用提供理论指导和实验依据。更为重要的是，本研究发现，XS007A的作用机制与EK1等融合抑制剂不同，其靶点并不是传统的病毒六螺旋靶点，而是宿主细胞的CPL蛋白酶，从而抑制病毒的内吞入侵途径，为研发高效广谱抗HCoVs的新型药物提供了重要线索和理论依据。在本课题的实施过程中，发表了SCI论文5篇，其中第一作者4篇。因此，已按要求完成了本课题的任务。