An engineered recombinant protein containing three structural domains in SARS-CoV-2 S2 protein has potential to act as a pan-human coronavirus entry inhibitor or vaccine antigen

Xinling Wang; Lujia Sun; Zezhong Liu; Lixiao Xing; Yun Zhu; Wei Xu; Shuai Xia; Lu Lu; Shibo Jiang

doi:10.1080/22221751.2023.2244084

An engineered recombinant protein containing three structural domains in SARS-CoV-2 S2 protein has potential to act as a pan-human coronavirus entry inhibitor or vaccine antigen

Emerg Microbes Infect. 2023 Dec;12(2):2244084. doi: 10.1080/22221751.2023.2244084.

Authors

Xinling Wang¹, Lujia Sun¹, Zezhong Liu^{1

2}, Lixiao Xing¹, Yun Zhu³, Wei Xu¹, Shuai Xia¹, Lu Lu¹, Shibo Jiang^{1

4}

Affiliations

¹ 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.
² Department of Pharmacology & Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai, People's Republic of China.
³ National Key Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, People's Republic of China.
⁴ Key Laboratory of Reproduction Regulation of National Population and Family Planning Commission, The Shanghai Institute of Planned Parenthood Research, Institute of Reproduction and Development, Fudan University, Shanghai, People's Republic of China.

Abstract

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.

Keywords: Coronavirus; entry inhibitor; pan-human coronavirus; stem helix; vaccine.

MeSH terms

Animals
COVID-19* / prevention & control
Coronavirus 229E, Human* / metabolism
Humans
Mice
Middle East Respiratory Syndrome Coronavirus* / genetics
Middle East Respiratory Syndrome Coronavirus* / metabolism
Recombinant Proteins / genetics
SARS-CoV-2 / genetics
SARS-CoV-2 / metabolism
Spike Glycoprotein, Coronavirus / chemistry

Substances

Recombinant Proteins
Spike Glycoprotein, Coronavirus
spike protein, SARS-CoV-2

Grants and funding

This work was supported by grants from the National Key R&D Program of China (2022YFC2604102 and 2021YFC2300703 to L.L.), National Natural Science Foundation of China (grant numbers 92169112 to S.J.; 82202491 to X.W.), Shanghai Municipal Science and Technology Major Project (ZD2021CY001 to S.J, L.L and S.X.), and Program of Shanghai Academic/Technology Research (20XD1420300 to L.L.).