Identification, optimization, and biological evaluation of 3-O-β-chacotriosyl ursolic acid derivatives as novel SARS-CoV-2 entry inhibitors by targeting the prefusion state of spike protein.
Li H, Cheng C, Shi S, Wu Y, Gao Y, Liu Z, Liu M, Li Z, Huo L, Pan X, Liu S, Song G.
The COVID-19 pandemic generates a global threat to public health and continuously emerging SARS-CoV-2 variants bring a great challenge to the development of both vaccines and antiviral agents. In this study, we identified UA-18 and its optimized analog UA-30 via the hit-to-lead strategy as novel SARS-CoV-2 fusion inhibitors. The lead compound UA-30 showed potent antiviral activity against infectious SARS-CoV-2 (wuhan-HU-1 variant) in Vero-E6 cells and was also effective against infection of diverse pseudotyped SARS-CoV-2 variants with mutations in the S protein including the Omicron and Delta variants. More importantly, UA-30 might target the cavity between S1 and S2 subunits to stabilize the prefusion state of the SARS-CoV-2 S protein, thus leading to interfering with virus-cell membrane fusion. This study offers a set of novel SARS-CoV-2 fusion inhibitors against SARS-CoV-2 and its variants based on the 3-O-β-chacotriosyl UA skeleton.