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

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-HU1 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-beta-chacotriosyl UA skeleton.

Automated summary

In this study, UA-18 and its optimized analog UA-30 were identified as novel SARS-CoV-2 fusion inhibitors. The lead compound UA-30 exhibited potent antiviral activity against infectious SARS-CoV-2 and its variants. The mechanism of action of UA-30 involves stabilizing the prefusion state of the SARS-CoV-2 S protein.