首页|Altered hACE2 binding affinity and S1/S2 cleavage efficiency of SARS-CoV-2 spike protein mutants affect viral cell entry

Altered hACE2 binding affinity and S1/S2 cleavage efficiency of SARS-CoV-2 spike protein mutants affect viral cell entry

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SARS-CoV-2 variants are constantly emerging,hampering public health measures in controlling the number of infections.While it is well established that mutations in spike proteins observed for the different variants directly affect virus entry into host cells,there remains a need for further expansion of systematic and multifaceted comparisons.Here,we comprehensively studied the effect of spike protein mutations on spike expression and proteolytic activation,binding affinity,viral entry efficiency and host cell tropism of eight variants of concern(VOC)and variants of interest(VOI).We found that both the full-length spike and its receptor-binding domain(RBD)of Omicron bind to hACE2 with an affinity similar to that of the wild-type.In addition,Alpha,Beta,Delta and Lambda pseudoviruses gained significantly enhanced cell entry ability compared to the wild-type,while the Omicron pseudoviruses showed a slightly increased cell entry,suggesting the vastly increased rate of transmission observed for Omicron variant is not associated with its affinity to hACE2.We also found that the spikes of Omicron and Mu showed lower S1/S2 cleavage efficiency and inefficiently utilized TMPRSS2 to enter host cells than others,suggesting that they prefer the endocytosis pathway to enter host cells.Furthermore,all variants'pseudoviruses we tested gained the ability to enter the animal ACE2-expressing cells.Especially the infection potential of rats and mice showed significantly increased,strongly suggesting that rodents possibly become a reservoir for viral evolution.The insights gained from this study provide valuable guidance for a targeted approach to epidemic control,and contribute to a better understanding of SARS-CoV-2 evolution.

SARS-CoV-2Variants of Concern(VOC)OmicronBinding affinityViral entryHost-tropism

Ke Wang、Yu Pan、Dianbing Wang、Ye Yuan、Min Li、Yuanyuan Chen、Lijun Bi、Xian-En Zhang

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National Key Laboratory of Biomacromolecules,Institute of Biophysics,Chinese Academy of Sciences,Beijing,100101,China

Faculty of Synthetic Biology,Shenzhen Institute of Advanced Technology,Shenzhen,518055,China

University of Chinese Academy of Sciences,Beijing,100101,China

Strategic Priority Research Program of the Chinese Academy of SciencesNational Key Research and Development Program of ChinaNational Key Research and Development Program of ChinaNational Key Research and Development Program of ChinaProgram of the Chinese Academy of Sciences

XDB290501002022YFC08699002022YFC23035012020YFC08611002020YJFK-Z-0150

2023

中国病毒学
中国科学院武汉病毒研究所,中国微生物学会

中国病毒学

CSTPCDCSCD
影响因子:0.393
ISSN:1674-0769
年,卷(期):2023.38(4)
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