Structure-aided optimization of 3-O-β-chacotriosyl epiursolic acid derivatives as novel H5N1 virus entry inhibitors
- Bioorg Med Chem Lett. 2020 Nov 15;30(22):127518. doi: 10.1016/j.bmcl.2020.127518.
- 1. Department of Human Anatomy, School of Medicine, Jinan University, Guangzhou 510632, China.
- 2. Department of Ophthalmology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510630, China.
- 3. College of Materials and Energy, South China Agricultural University, Guangzhou 510642, China.
- 4. School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.
- 5. School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China. Electronic address: [email protected].
- 6. College of Materials and Energy, South China Agricultural University, Guangzhou 510642, China. Electronic address: [email protected].
It is urgent to develop new Antiviral agents due to the continuous emergence of drug-resistant strains of Influenza Virus. Our earlier studies have identified that certain pentacyclic triterpene saponins with 3-O-β-chacotriosyl residue are novel H5N1 virus entry inhibitors. In the present study, a series of C-28 modified 3-O-β-chacotriosyl epiursolic acid derivatives via conjugation with different kinds of sides were synthesized, of which anti-H5N1 activities in A549 cells were evaluated in vitro. Among them, 10 exhibited strongest anti-H5N1 potency at the low-micromole level without cytotoxicity, surpassing the potency of ribavirin. Further mechanism studies of the lead compound 10 based on HI, SPR and molecular modeling revealed that these new 3-epiursolic acid saponins could bind tightly to the viral envelope HA protein, thus blocking the invasion of H5N1 viruses into host cells.