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antiviral efficacy; however, emerging SARS-CoV-2 variants could substantially compromise its neutralization effectiveness. In this study, we constructed two multivalent LCB1 fusion proteins termed LCB1T and LCB1T-Fc, and characterized their potency in inhibiting SARS-CoV-2 pseudovirus and authentic virus in vitro. In the inhibition of various SARS-CoV-2 variants, the two LCB1 fusion proteins exhibited markedly improved inhibitory activities compared to LCB1 as anticipated; however, it was observed that relative to the D614G mutation hosting variant, the variants Delta, Lambda, and Omicron BQ.1.1, XBB, XBB.1.5, and EG.5.1 caused various degrees of resistance to the two fusion proteins\u2019 inhibition, with XBB, XBB.1.5, and EG.5.1 variants showing high-level resistance. Moreover, we demonstrated that bat coronavirus RaTG13 and pangolin coronavirus PCoV-GD\/PCoV-GX were highly sensitive to two LCB1 fusion proteins, but not LCB1, inhibition. Importantly, our findings revealed a notable decrease in the blocking capacity of the multivalent LCB1 inhibitor on the interaction between the virus\u2019s RBD\/S and the cell receptor ACE2 when confronted with the XBB variant compared to WT and the Omicron BA.1 variant. In conclusion, our studies provide valuable insights into the antiviral profiling of multivalent LCB1 inhibitors and offer a promising avenue for the development of novel broad-spectrum antiviral therapeutics.<\/jats:p>","DOI":"10.3390\/v16010036","type":"journal-article","created":{"date-parts":[[2023,12,25]],"date-time":"2023-12-25T23:00:12Z","timestamp":1703545212000},"page":"36","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Susceptibility and Resistance of SARS-CoV-2 Variants to LCB1 and Its Multivalent Derivatives"],"prefix":"10.3390","volume":"16","author":[{"given":"Hongliang","family":"Jin","sequence":"first","affiliation":[{"name":"NHC Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 102600, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yani","family":"Gong","sequence":"additional","affiliation":[{"name":"NHC Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 102600, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Cheng","sequence":"additional","affiliation":[{"name":"Institute of Hepatology, National Clinical Research Center for Infectious Disease, Shenzhen Third People\u2019s Hospital, The Second Affiliated Hospital, School of Medicine, Southern University of Science and Technology, Shenzhen 518112, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanmei","family":"Zhu","sequence":"additional","affiliation":[{"name":"NHC Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 102600, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zheng","family":"Zhang","sequence":"additional","affiliation":[{"name":"Institute of Hepatology, National Clinical Research Center for Infectious Disease, Shenzhen Third People\u2019s Hospital, The Second Affiliated Hospital, School of Medicine, Southern University of Science and Technology, Shenzhen 518112, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2048-6696","authenticated-orcid":false,"given":"Yuxian","family":"He","sequence":"additional","affiliation":[{"name":"NHC Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 102600, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,12,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"101049","DOI":"10.1016\/j.xcrm.2023.101049","article-title":"Neutralization escape of Omicron XBB, BR.2, and BA.2.3.20 subvariants","volume":"4","author":"Faraone","year":"2023","journal-title":"Cell Rep. 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