Structure-aided optimization of 3-O-β-chacotriosyl ursolic acid as novel H5N1 entry inhibitors with high selective index

Yixian Liao; Lizhu Chen; Sumei Li; Zi-Ning Cui; Zhiwei Lei; Hui Li; Shuwen Liu; Gaopeng Song

doi:10.1016/j.bmc.2019.07.028

Structure-aided optimization of 3-O-β-chacotriosyl ursolic acid as novel H5N1 entry inhibitors with high selective index

Bioorg Med Chem. 2019 Sep 15;27(18):4048-4058. doi: 10.1016/j.bmc.2019.07.028. Epub 2019 Jul 19.

Authors

Yixian Liao¹, Lizhu Chen², Sumei Li³, Zi-Ning Cui⁴, Zhiwei Lei⁵, Hui Li⁶, Shuwen Liu⁷, Gaopeng Song⁸

Affiliations

¹ College of Materials and Energy, South China Agricultural University, Guangzhou 510642, China; State Key Laboratory for Conservation and Utilization of Subtropical Agro-bioresources, Integrative Microbiology Research Centre, Guangdong Province Key Laboratory of Microbial Signals and Disease Control, South China Agricultural University, Guangzhou 510642, China.
² School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.
³ Department of Human Anatomy, School of Medicine, Jinan University, Guangzhou 510632, China.
⁴ State Key Laboratory for Conservation and Utilization of Subtropical Agro-bioresources, Integrative Microbiology Research Centre, Guangdong Province Key Laboratory of Microbial Signals and Disease Control, South China Agricultural University, Guangzhou 510642, China.
⁵ Guizhou Tea Reasearch Institute, Guizhou Academy of Agricultural Science, Guiyang, Guizhou 550006, China.
⁶ College of Materials and Energy, South China Agricultural University, Guangzhou 510642, China.
⁷ School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China. Electronic address: liusw@smu.edu.cn.
⁸ College of Materials and Energy, South China Agricultural University, Guangzhou 510642, China. Electronic address: songgp1021@scau.edu.cn.

PMID: 31350154
DOI: 10.1016/j.bmc.2019.07.028

Abstract

Currently, entry inhibitors contribute immensely in developing a new generation of anti-influenza virus drugs. Our earlier studies have identified that 3-O-β-chacotriosyl ursolic acid (1) could inhibit H5N1 pseudovirus by targeting hemagglutinin (HA). In the present study, a series of C-28 modified pentacyclic triterpene saponins via conjugation with a series of amide derivatives were synthesized and their antiviral activities against influenza A/Duck/Guangdong/99 virus (H5N1) in MDCK cells were evaluated. The SARs analysis of these compounds revealed that introduction of certain amide structures at the 17-COOH of ursolic acid could significantly enhance both their antiviral activity and selective index. This study indicated that the attachment of the methoxy group or Cl atom to the phenyl ring at the ortho- or para-position was crucial to improve inhibitory activity. Mechanism studies demonstrated that these title triterpenoids could bind tightly to the viral envelope HA to block the attachment of viruses to host cells, which was consistent with docking studies.

Keywords: 3-O-β-chacotriosyl pentacyclic triterpenoids; H5N1 entry inhibitors; Structure-activity relationships.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents, Phytogenic / pharmacology
Antineoplastic Agents, Phytogenic / therapeutic use*
Humans
Influenza A Virus, H5N1 Subtype / drug effects*
Structure-Activity Relationship
Triterpenes / pharmacology
Triterpenes / therapeutic use*
Ursolic Acid

Substances

Antineoplastic Agents, Phytogenic
Triterpenes