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Resistance profile and mechanism of severe acute respiratory syndrome coronavirus-2 variants to LCB1 inhibitor targeting the spike receptor-binding motif

LCB1 is a 56-mer miniprotein computationally designed to target the spike (S) receptor-binding motif of SARS-CoV-2 with potent in vitro and in vivo inhibitory activities (Cao et al., 2020; Case et al., 2021). However, the rapid emergence and epidemic of viral variants have greatly impacted the effec...

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Autores principales: Wu, Tong, Zhu, Yuanmei, Liu, Nian, Hu, Yue, Chong, Huihui, He, Yuxian
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9593036/
https://www.ncbi.nlm.nih.gov/pubmed/36304946
http://dx.doi.org/10.3389/fmicb.2022.1022006
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author Wu, Tong
Zhu, Yuanmei
Liu, Nian
Hu, Yue
Chong, Huihui
He, Yuxian
author_facet Wu, Tong
Zhu, Yuanmei
Liu, Nian
Hu, Yue
Chong, Huihui
He, Yuxian
author_sort Wu, Tong
collection PubMed
description LCB1 is a 56-mer miniprotein computationally designed to target the spike (S) receptor-binding motif of SARS-CoV-2 with potent in vitro and in vivo inhibitory activities (Cao et al., 2020; Case et al., 2021). However, the rapid emergence and epidemic of viral variants have greatly impacted the effectiveness of S protein-targeting vaccines and antivirals. In this study, we chemically synthesized a peptide-based LCB1 inhibitor and characterized the resistance profile and underlying mechanism of SARS-CoV-2 variants. Among five variants of concern (VOCs), we found that pseudoviruses of Beta, Gamma, and Omicron were highly resistant to the LCB1 inhibition, whereas the pseudoviruses of Alpha and Delta as well as the variant of interest (VOI) Lambda only caused mild resistance. By generating a group of mutant viruses carrying single or combination mutations, we verified that K417N and N501Y substitutions in RBD critically determined the high resistance phenotype of VOCs. Furthermore, a large panel of 85 pseudoviruses with naturally occurring RBD point-mutations were generated and applied to LCB1, which identified that E406Q, K417N, and L455F conferred high-levels of resistance, when Y505W caused a ∼6-fold resistance fold-change. We also showed that the resistance mutations could greatly weaken the binding affinity of LCB1 to RBD and thus attenuated its blocking capacity on the interaction between RBD and the cell receptor ACE2. In conclusion, our data have provided crucial information for understanding the mechanism of SARS-CoV-2 resistance to LCB1 and will guide the design strategy of novel LCB1-based antivirals against divergent VOCs and evolutionary mutants.
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spelling pubmed-95930362022-10-26 Resistance profile and mechanism of severe acute respiratory syndrome coronavirus-2 variants to LCB1 inhibitor targeting the spike receptor-binding motif Wu, Tong Zhu, Yuanmei Liu, Nian Hu, Yue Chong, Huihui He, Yuxian Front Microbiol Microbiology LCB1 is a 56-mer miniprotein computationally designed to target the spike (S) receptor-binding motif of SARS-CoV-2 with potent in vitro and in vivo inhibitory activities (Cao et al., 2020; Case et al., 2021). However, the rapid emergence and epidemic of viral variants have greatly impacted the effectiveness of S protein-targeting vaccines and antivirals. In this study, we chemically synthesized a peptide-based LCB1 inhibitor and characterized the resistance profile and underlying mechanism of SARS-CoV-2 variants. Among five variants of concern (VOCs), we found that pseudoviruses of Beta, Gamma, and Omicron were highly resistant to the LCB1 inhibition, whereas the pseudoviruses of Alpha and Delta as well as the variant of interest (VOI) Lambda only caused mild resistance. By generating a group of mutant viruses carrying single or combination mutations, we verified that K417N and N501Y substitutions in RBD critically determined the high resistance phenotype of VOCs. Furthermore, a large panel of 85 pseudoviruses with naturally occurring RBD point-mutations were generated and applied to LCB1, which identified that E406Q, K417N, and L455F conferred high-levels of resistance, when Y505W caused a ∼6-fold resistance fold-change. We also showed that the resistance mutations could greatly weaken the binding affinity of LCB1 to RBD and thus attenuated its blocking capacity on the interaction between RBD and the cell receptor ACE2. In conclusion, our data have provided crucial information for understanding the mechanism of SARS-CoV-2 resistance to LCB1 and will guide the design strategy of novel LCB1-based antivirals against divergent VOCs and evolutionary mutants. Frontiers Media S.A. 2022-10-11 /pmc/articles/PMC9593036/ /pubmed/36304946 http://dx.doi.org/10.3389/fmicb.2022.1022006 Text en Copyright © 2022 Wu, Zhu, Liu, Hu, Chong and He. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Microbiology
Wu, Tong
Zhu, Yuanmei
Liu, Nian
Hu, Yue
Chong, Huihui
He, Yuxian
Resistance profile and mechanism of severe acute respiratory syndrome coronavirus-2 variants to LCB1 inhibitor targeting the spike receptor-binding motif
title Resistance profile and mechanism of severe acute respiratory syndrome coronavirus-2 variants to LCB1 inhibitor targeting the spike receptor-binding motif
title_full Resistance profile and mechanism of severe acute respiratory syndrome coronavirus-2 variants to LCB1 inhibitor targeting the spike receptor-binding motif
title_fullStr Resistance profile and mechanism of severe acute respiratory syndrome coronavirus-2 variants to LCB1 inhibitor targeting the spike receptor-binding motif
title_full_unstemmed Resistance profile and mechanism of severe acute respiratory syndrome coronavirus-2 variants to LCB1 inhibitor targeting the spike receptor-binding motif
title_short Resistance profile and mechanism of severe acute respiratory syndrome coronavirus-2 variants to LCB1 inhibitor targeting the spike receptor-binding motif
title_sort resistance profile and mechanism of severe acute respiratory syndrome coronavirus-2 variants to lcb1 inhibitor targeting the spike receptor-binding motif
topic Microbiology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9593036/
https://www.ncbi.nlm.nih.gov/pubmed/36304946
http://dx.doi.org/10.3389/fmicb.2022.1022006
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