A pan-coronavirus fusion inhibitor targeting the HR1 domain of human coronavirus spike
A pan-coronavirus fusion inhibitor targeting the HR1 domain of human coronavirus spike
复制标题
一种针对人类冠状病毒刺突HR1结构域的泛冠状病毒融合抑制剂
DOI：
10.1126/sciadv.aav4580
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发表时间：
2019-04-01
期刊：
影响因子：
13.6
通讯作者：
Lu, Lu
中科院分区：
文献类型：
--
作者：
Xia, Shuai;Yan, Lei;Lu, Lu
EK1是一种广谱人冠状病毒融合抑制剂，用于对抗当前和新出现的冠状病毒感染。正如过去SARS-CoV和中东呼吸综合征- cov疫情所表明的那样，不断出现的高致病性人类冠状病毒（hcov）仍然对人类健康构成重大威胁。开发具有广谱HCoV抑制活性的药物将解决这一迫切的未满足的医疗需求。虽然已有研究表明HCoV刺突(S)蛋白的HR1是抑制特异性HCoV的重要靶点，但这一保守区域能否作为开发广谱泛cov抑制剂的靶点仍存在争议。在这里，我们发现从HCoV-OC43的HR2结构域衍生的肽OC43-HR2P对多种hcov具有广泛的融合抑制活性。优化后的OC43-HR2P形式的EK1具有显著提高的泛冠状病毒融合抑制活性和药物性能。晶体结构表明，EK1可以与短α-HCoV和长β-HCoV HR1s形成稳定的六螺旋束结构，进一步支持了HR1区域作为泛冠病毒靶点的作用。
EK1 is a broad-spectrum human coronavirus fusion inhibitor for combating infection of current and emerging coronaviruses. Continuously emerging highly pathogenic human coronaviruses (HCoVs) remain a major threat to human health, as illustrated in past SARS-CoV and MERS-CoV outbreaks. The development of a drug with broad-spectrum HCoV inhibitory activity would address this urgent unmet medical need. Although previous studies have suggested that the HR1 of HCoV spike (S) protein is an important target site for inhibition against specific HCoVs, whether this conserved region could serve as a target for the development of broad-spectrum pan-CoV inhibitor remains controversial. Here, we found that peptide OC43-HR2P, derived from the HR2 domain of HCoV-OC43, exhibited broad fusion inhibitory activity against multiple HCoVs. EK1, the optimized form of OC43-HR2P, showed substantially improved pan-CoV fusion inhibitory activity and pharmaceutical properties. Crystal structures indicated that EK1 can form a stable six-helix bundle structure with both short α-HCoV and long β-HCoV HR1s, further supporting the role of HR1 region as a viable pan-CoV target site.