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
em En
| MEDLINE
| ID: mdl-36508939
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.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Ácido Oleanólico
/
Saponinas
/
Viroses
/
Inibidores da Fusão de HIV
/
COVID-19
Limite:
Humans
Idioma:
En
Ano de publicação:
2023
Tipo de documento:
Article