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

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.

Identification of N- and C-3-Modified Laudanosoline Derivatives as Novel Influenza PAN Endonuclease Inhibitors.

Influenza PAN inhibitors are of particular importance in current efforts to develop a new generation of antiviral drugs due to the growing emergence of highly pathogenic influenza viruses and the resistance to existing antiviral inhibitors. Herein, we design and synthesize a set of 1,3-cis-N-substituted-1,2,3,4-tetrahydroisoquinoline derivatives to enhance their potency by further exploiting the pockets 3 and 4 in the PAN endonuclease based on the hit d,l-laudanosoline. Particularly, the lead compound 35 exhibited potent and broad anti-influenza virus effects with EC50 values ranging from 0.43 to 1.12 µM in vitro and good inhibitory activity in a mouse model. Mechanistic studies demonstrated that 35 could bind tightly to the PAN endonuclease of RNA-dependent RNA polymerase, thus blocking the viral replication to exert antiviral activity. Overall, our study might establish the importance of 1,2,3,4-tetrahydroisoquinoline-6,7-diol-based derivatives for the development of novel PAN inhibitors of influenza viruses.