Structure-aided optimization of 3-O-β-chacotriosyl epiursolic acid derivatives as novel H5N1 virus entry inhibitors. Issue 22 (15th November 2020)

• Record Type: Journal Article
• Authors: Li, Sumei; Jia, Xiuhua; Li, Hui; Ye, Yilu; Zhang, Xuesha; Gao, Yongfeng; Guo, Guoqing; Liu, Shuwen; Song, Gaopeng
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 30:Issue 22(2020)
• Publication Date: 2020-11-15
• Subjects: 3-Epiursolic acid saponins -- Semi-synthesis -- H5N1 entry inhibitors -- Structure–activity relationships; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2020.127518
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Highlights: A series of 3-O-β-chacotriosyl epiursolic acid derivatives were synthesized. These saponins showed strong anti-H5N1 activity in vitro . Intensive SARs studies were conducted. These saponins could block the invasion of H5N1 viruses into host cells. Abstract: 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.