Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Shanghai Institute of Infectious Disease and Biosecurity, Shanghai Frontiers Science Center of Pathogenic Microbes and Infection, Fudan University, Shanghai, People's Republic of China.
Department of Pharmacology & Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai, People's Republic of China.
Emerg Microbes Infect. 2023 Dec;12(2):2244084. doi: 10.1080/22221751.2023.2244084.
The threat to global health caused by three highly pathogenic human coronaviruses (HCoV), SARS-CoV-2, MERS-CoV and SARS-CoV, calls for the development of pan-HCoV therapeutics and vaccines. This study reports the design and engineering of a recombinant protein designated HR1LS. It contains three linked molecules, each consisting of three structural domains, including a heptad repeat 1 (HR1), a central helix (CH), and a stem helix (SH) region, in the S2 subunit of SARS-CoV-2 spike (S) protein. It was found that HR1LS protein automatically formed a trimer able to bind with heptad repeat 2 (HR2) region in the SARS-CoV-2 S2 subunit, thus potently inhibiting HCoV fusion and entry into host cells. Furthermore, immunization of mice with HR1LS, when combined with CF501 adjuvant, resulted in the production of neutralizing antibodies against infection of SARS-CoV-2 and its variants, as well as SARS-CoV, MERS-CoV, HCoV-229E, HCoV-NL63 and MjHKU4r-CoV-1. These results suggest that HR1LS is a promising candidate for further development as a novel HR1-trimer-based pan-HCoV entry inhibitor or vaccine for the treatment and prevention of infection by SARS-CoV-2 and its variants, but also other HCoVs with the potential to cause future emerging and re-emerging infectious coronavirus diseases.
三种高致病性人类冠状病毒（HCoV）——SARS-CoV-2、MERS-CoV 和 SARS-CoV——对全球健康构成威胁，这就需要开发针对所有 HCoV 的治疗方法和疫苗。本研究报告了一种名为 HR1LS 的重组蛋白的设计和工程。它包含三个连接的分子，每个分子由 SARS-CoV-2 刺突（S）蛋白 S2 亚基中的三个结构域组成，包括一个七肽重复 1（HR1）、一个中心螺旋（CH）和一个茎螺旋（SH）区域。研究发现，HR1LS 蛋白自动形成三聚体，能够与 SARS-CoV-2 S2 亚基中的七肽重复 2（HR2）区域结合，从而有效地抑制 HCoV 融合和进入宿主细胞。此外，用 HR1LS 免疫小鼠，并结合 CF501 佐剂，可产生针对 SARS-CoV-2 及其变体以及 SARS-CoV、MERS-CoV、HCoV-229E、HCoV-NL63 和 MjHKU4r-CoV-1 感染的中和抗体。这些结果表明，HR1LS 是一种很有前途的候选物，可以进一步开发为新型基于 HR1 三聚体的泛 HCoV 进入抑制剂或疫苗，用于治疗和预防 SARS-CoV-2 及其变体以及其他具有潜在引发未来新发和再发冠状病毒病的 HCoV 的感染。
