Structure-activity relationships of 3-O-β-chacotriosyl oleanane-type triterpenoids as potential H5N1 entry inhibitors

  • Eur J Med Chem. 2016 Aug 25:119:109-21. doi: 10.1016/j.ejmech.2016.04.061.
Gaopeng Song  1 ,  Xintian Shen  2 ,  Sumei Li  3 ,  Yibin Li  4 ,  Hongzong Si  5 ,  Jihong Fan  4 ,  Junhua Li  4 ,  Erqiang Gao  4 ,  Shuwen Liu  6
Affiliations
  • 1. College of Materials and Energy, South China Agricultural University, Guangzhou, 510642, China. Electronic address: [email protected].
  • 2. Department of Pharmacy, Maternal and Child Health Hospital of Bao'an District, Shenzhen, 518133, China; School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China.
  • 3. Department of Human Anatomy, School of Medicine, Jinan University, Guangzhou, 510632, China.
  • 4. College of Materials and Energy, South China Agricultural University, Guangzhou, 510642, China.
  • 5. Institute for Computational Science and Engineering, Qingdao University, Qingdao, 266071, China.
  • 6. Department of Pharmacy, Maternal and Child Health Hospital of Bao'an District, Shenzhen, 518133, China. Electronic address: [email protected].
PMID: 27153348 DOI: 10.1016/j.ejmech.2016.04.061
Abstract

A series of 3-O-β-chacotriosyl oleanolic acid analogs have been designed, synthesized and evaluated as H5N1 entry inhibitors based on a small molecule inhibitor saponin 1 previously discovered by us. Detailed structure-activity relationships (SARs) studies on the aglycone of compound 1 indicated that the subtle modification of oleanolic acid as an aglycon has key influences on the Antiviral activity. These results suggested that either the introduction of a disubstituted amide structure at the 17-COOH of OA or alteration of the C-3 configuration of OA from 3β-to 3α-forms can significantly improve the selective index while maintaining their Antiviral activities in vitro. Compound 8 was selected for further mechanistic study because of its distinguished inhibition activity and good selective index. Molecular simulation study and surface plasmon resonance analysis confirmed that compound 8 stabilized HA2 subunit of hemagglutinin (HA) by binding with amino acid residues LYS-26, ASN-53, ASN-27 and ASN-50, therefore may prevent HA from conformational rearranging, which is a critical step for viral entry.

Keywords
3-O-β-chacotriosyl saponins; H5N1 entry inhibitors; Structure-activity relationships.