Discovery and structural optimization of 3-O-ß-Chacotriosyl betulonic acid saponins as potent fusion inhibitors of Omicron virus infections.
Bioorg Chem
; 131: 106316, 2023 02.
Article
in English
| MEDLINE | ID: covidwho-2149385
ABSTRACT
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 EC50 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.
Keywords
Full text:
Available
Collection:
International databases
Database:
MEDLINE
Main subject:
Oleanolic Acid
/
Saponins
/
Virus Diseases
/
HIV Fusion Inhibitors
/
COVID-19
Topics:
Variants
Limits:
Humans
Language:
English
Journal:
Bioorg Chem
Year:
2023
Document Type:
Article
Affiliation country:
J.bioorg.2022.106316
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