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SARS-CoV-2 Omicron viruses possess a high antigenic shift, and the approved anti-SARS-CoV-2 drugs are extremely limited, which makes the development of new antiviral drugs for the clinical treatment and prevention of SARS-CoV-2 outbreaks imperative. We have previously discovered a new series of markedly potent small-molecule inhibitors of SARS-CoV-2 virus entry, exampled by the hit compound 2. Here, we report a further study of bioisosteric replacement of the eater linker at the C-17 position of 2 with a variety of aromatic amine moieties, followed by a focused structure-activity relationship study, leading to the discovery of a series of novel 3- O - β -chacotriosyl BA amide derivatives as small-molecule Omicron fusion inhibitors with improved potency and selectivity index. Particularly, our medicinal chemistry efforts have resulted in a potent, and efficacious lead compound S-10 with appreciable pharmacokinetic properties, which exhibited broad-spectrum potency against Omicron and other variants with EC 50 values ranging from 0.82 to 5.45 μM. Mutagenesis studies confirmed that inhibition of Omicron viral entry was mediated by the direct interaction with S in the prefusion state. These results reveal that S-10 is suitable for further optimization as Omicron fusion inhibitors, with the potential to be developed as therapeutic agents for the treatment and control of SARS-CoV-2 ant its variants infections. [Display omitted] • A set of 3- O -β-chacotriosyl BA saponins were synthesized and characterized based on the bioisosterism and SBDD strategies. • These title saponins exhibited strong inhibition toward Omicron. • Intensive structure-activity relationships were conducted. • S-10 showed broad-spectrum anti-SARS-CoV-2 activities by blocking membrane fusion. • S-10 displayed promising pharmacokinetic properties in vitro. [ABSTRACT FROM AUTHOR]

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. [Display omitted] • A set of 3-O-β-chacotriosyl UA saponins were synthesized and characterized. • These saponins showed potent inhibition toward diverse pseudotyped SARS-CoV-2 variants with mutations in S. • Intensive structure-activity relationships were conducted. • Lead compound UA-30 displayed improved anti-SARS-CoV-2 activity in vitro and SI. • UA-30 was shown to bind to SARS-CoV-2 S2 protein directly and block the prefusion state of spike protein. [ABSTRACT FROM AUTHOR]