Discovery and structural optimization of 3-O-β-Chacotriosyl betulonic acid saponins as potent fusion inhibitors of Omicron virus infections.

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.

SUBMITTER: Liu M 

PROVIDER: S-EPMC9729598 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature