title: Structure-activity relationships of 3-O-β-chacotriosyl oleanane-type triterpenoids as potential H5N1 entry inhibitors.
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.
authors.affiliation: College of Materials and Energy, South China Agricultural University, Guangzhou, 510642, China. Electronic address: vinsin1021@126.com.
authors.forename: Gaopeng
authors.initials: G
authors.lastname: Song
authors.affiliation: 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.
authors.forename: Xintian
authors.initials: X
authors.lastname: Shen
authors.affiliation: Department of Human Anatomy, School of Medicine, Jinan University, Guangzhou, 510632, China.
authors.forename: Sumei
authors.initials: S
authors.lastname: Li
authors.affiliation: College of Materials and Energy, South China Agricultural University, Guangzhou, 510642, China.
authors.forename: Yibin
authors.initials: Y
authors.lastname: Li
authors.affiliation: Institute for Computational Science and Engineering, Qingdao University, Qingdao, 266071, China.
authors.forename: Hongzong
authors.initials: H
authors.lastname: Si
authors.affiliation: College of Materials and Energy, South China Agricultural University, Guangzhou, 510642, China.
authors.forename: Jihong
authors.initials: J
authors.lastname: Fan
authors.affiliation: College of Materials and Energy, South China Agricultural University, Guangzhou, 510642, China.
authors.forename: Junhua
authors.initials: J
authors.lastname: Li
authors.affiliation: College of Materials and Energy, South China Agricultural University, Guangzhou, 510642, China.
authors.forename: Erqiang
authors.initials: E
authors.lastname: Gao
authors.affiliation: Department of Pharmacy, Maternal and Child Health Hospital of Bao'an District, Shenzhen, 518133, China. Electronic address: liusw@smu.edu.cn.
authors.forename: Shuwen
authors.initials: S
authors.lastname: Liu
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D002645:Chickens; D004285:Dogs; D004912:Erythrocytes / Q000378:metabolism; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000737:chemistry / Q000378:metabolism; D053124:Influenza A Virus, H5N1 Subtype / Q000187:drug effects* / Q000502:physiology; D061985:Madin Darby Canine Kidney Cells; D062105:Molecular Docking Simulation; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000737:chemistry; D020836:Protein Structure, Quaternary; D013329:Structure-Activity Relationship; D014315:Triterpenes / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D053586:Virus Internalization / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D014315:Triterpenes; C483468:hemagglutinin, human influenza A virus; C413246:oleanane; D009828:Oleanolic Acid
keywords: 3-O-β-chacotriosyl saponins; H5N1 entry inhibitors; Structure-activity relationships