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Discovery and structural optimization of 3-O-β-Chacotriosyl betulonic acid saponins as potent fusion inhibitors of Omicron virus infections
The recent global Omicron epidemics underscore the great need for the development of small molecule therapeutics with appropriate mechanisms. The trimeric spike protein (S) of SARS-CoV-2 plays a pivotal role in mediating viral entry into host cells. We continued our efforts to develop small-molecule...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier Inc.
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9729598/ https://www.ncbi.nlm.nih.gov/pubmed/36508939 http://dx.doi.org/10.1016/j.bioorg.2022.106316 |
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author | Liu, Mingjian Wang, Jinshen Wan, Xin Li, Baixi Guan, Mingming Ning, Xiaoyun Hu, Xiaojie Li, Sumei Liu, Shuwen Song, Gaopeng |
author_facet | Liu, Mingjian Wang, Jinshen Wan, Xin Li, Baixi Guan, Mingming Ning, Xiaoyun Hu, Xiaojie Li, Sumei Liu, Shuwen Song, Gaopeng |
author_sort | Liu, Mingjian |
collection | PubMed |
description | The recent global Omicron epidemics underscore the great need for the development of small molecule therapeutics with appropriate mechanisms. The trimeric spike protein (S) of SARS-CoV-2 plays a pivotal role in mediating viral entry into host cells. We continued our efforts to develop small-molecule SARS-CoV-2 entry inhibitors. In this work, two sets of BA derivatives were designed and synthesized based on the hit BA-1 that was identified as a novel SARS-CoV-2 entry inhibitor. Compound BA-4, the most potent one, showed broad inhibitory activities against pOmicron and other pseudotyped variants with EC(50) values ranging 2.73 to 5.19 μM. Moreover, pSARS-CoV-2 assay, SPR analysis, Co-IP assay and the cell–cell fusion assay coupled with docking and mutagenesis studies revealed that BA-4 could stabilize S in the pre-fusion step to interfere with the membrane fusion, thereby displaying promising inhibition against Omicron entry. |
format | Online Article Text |
id | pubmed-9729598 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Elsevier Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-97295982022-12-08 Discovery and structural optimization of 3-O-β-Chacotriosyl betulonic acid saponins as potent fusion inhibitors of Omicron virus infections Liu, Mingjian Wang, Jinshen Wan, Xin Li, Baixi Guan, Mingming Ning, Xiaoyun Hu, Xiaojie Li, Sumei Liu, Shuwen Song, Gaopeng Bioorg Chem Article The recent global Omicron epidemics underscore the great need for the development of small molecule therapeutics with appropriate mechanisms. The trimeric spike protein (S) of SARS-CoV-2 plays a pivotal role in mediating viral entry into host cells. We continued our efforts to develop small-molecule SARS-CoV-2 entry inhibitors. In this work, two sets of BA derivatives were designed and synthesized based on the hit BA-1 that was identified as a novel SARS-CoV-2 entry inhibitor. Compound BA-4, the most potent one, showed broad inhibitory activities against pOmicron and other pseudotyped variants with EC(50) values ranging 2.73 to 5.19 μM. Moreover, pSARS-CoV-2 assay, SPR analysis, Co-IP assay and the cell–cell fusion assay coupled with docking and mutagenesis studies revealed that BA-4 could stabilize S in the pre-fusion step to interfere with the membrane fusion, thereby displaying promising inhibition against Omicron entry. Elsevier Inc. 2023-02 2022-12-08 /pmc/articles/PMC9729598/ /pubmed/36508939 http://dx.doi.org/10.1016/j.bioorg.2022.106316 Text en © 2022 Elsevier Inc. All rights reserved. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. |
spellingShingle | Article Liu, Mingjian Wang, Jinshen Wan, Xin Li, Baixi Guan, Mingming Ning, Xiaoyun Hu, Xiaojie Li, Sumei Liu, Shuwen Song, Gaopeng Discovery and structural optimization of 3-O-β-Chacotriosyl betulonic acid saponins as potent fusion inhibitors of Omicron virus infections |
title | Discovery and structural optimization of 3-O-β-Chacotriosyl betulonic acid saponins as potent fusion inhibitors of Omicron virus infections |
title_full | Discovery and structural optimization of 3-O-β-Chacotriosyl betulonic acid saponins as potent fusion inhibitors of Omicron virus infections |
title_fullStr | Discovery and structural optimization of 3-O-β-Chacotriosyl betulonic acid saponins as potent fusion inhibitors of Omicron virus infections |
title_full_unstemmed | Discovery and structural optimization of 3-O-β-Chacotriosyl betulonic acid saponins as potent fusion inhibitors of Omicron virus infections |
title_short | Discovery and structural optimization of 3-O-β-Chacotriosyl betulonic acid saponins as potent fusion inhibitors of Omicron virus infections |
title_sort | discovery and structural optimization of 3-o-β-chacotriosyl betulonic acid saponins as potent fusion inhibitors of omicron virus infections |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9729598/ https://www.ncbi.nlm.nih.gov/pubmed/36508939 http://dx.doi.org/10.1016/j.bioorg.2022.106316 |
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