title: Design, synthesis and biological evaluation of novel L-ascorbic acid-conjugated pentacyclic triterpene derivatives as potential influenza virus entry inhibitors.
abstract: Since the influenza viruses can rapidly evolve, it is urgently required to develop novel anti-influenza agents possessing a novel mechanism of action. In our previous study, two pentacyclic triterpene derivatives (Q8 and Y3) have been found to have anti-influenza virus entry activities. Keeping the potential synergy of biological activity of pentacyclic triterpenes and l-ascorbic acid in mind, we synthesized a series of novel l-ascorbic acid-conjugated pentacyclic triterpene derivatives (18-26, 29-31, 35-40 and 42-43). Moreover, we evaluated these novel compounds for their anti-influenza activities against A/WSN/33 virus in MDCK cells. Among all evaluated compounds, the 2,3-O,O-dibenzyl-6-deoxy-l-ascorbic acid-betulinic acid conjugate (30) showed the most significant anti-influenza activity with an EC50 of 8.7 μM, and no cytotoxic effects on MDCK cells were observed. Time-of-addition assay indicated that compound 30 acted at an early stage of the influenza life cycle. Further analyses revealed that influenza virus-induced hemagglutination of chicken red blood cells was inhibited by treatment of compound 30, and the interaction between the influenza hemagglutinin (HA) and compound 30 was determined by surface plasmon resonance (SPR) with a dissociation constant of KD = 3.76 μM. Finally, silico docking studies indicated that compound 30 and its derivative 31 were able to occupy the binding pocket of HA for sialic acid receptor. Collectively, these results suggested that l-ascorbic acid-conjugated pentacyclic triterpenes were promising anti-influenza entry inhibitors, and HA protein associated with viral entry was a promising drug target.
authors: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
authors: Han
authors: H
authors: Wang
authors: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
authors: Renyang
authors: R
authors: Xu
authors: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
authors: Yongying
authors: Y
authors: Shi
authors: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
authors: Longlong
authors: L
authors: Si
authors: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
authors: Pingxuan
authors: P
authors: Jiao
authors: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
authors: Zibo
authors: Z
authors: Fan
authors: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
authors: Xu
authors: X
authors: Han
authors: Institute of Systems Biomedicine, Department of Pathology, School of Basic Medical Sciences, Beijing Key Laboratory of Tumor Systems Biology, Peking University, Beijing 100191, China.
authors: Xingyu
authors: X
authors: Wu
authors: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
authors: Xiaoshu
authors: X
authors: Zhou
authors: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China; Medical Faculty of Kunming University of Science and Technology, Kunming 650500, China.
authors: Fei
authors: F
authors: Yu
authors: Institut Parisien de Chimie Moléculaire, CNRS UMR 8232, Université Pierre & Marie Curie-Paris 6, 4 Place Jussieu, 75005 Paris, France.
authors: Yongmin
authors: Y
authors: Zhang
authors: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
authors: Liangren
authors: L
authors: Zhang
authors: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
authors: Lihe
authors: L
authors: Zhang
authors: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China. Electronic address: deminzhou@bjmu.edu.cn.
authors: Demin
authors: D
authors: Zhou
authors: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China. Electronic address: slxiao@bjmu.edu.cn.
authors: Sulong
authors: S
authors: Xiao
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D001205:Ascorbic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*; D004285:Dogs; D015195:Drug Design; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000378:metabolism; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000187:drug effects* / Q000502:physiology; D007251:Influenza, Human / Q000188:drug therapy / Q000821:virology; D061985:Madin Darby Canine Kidney Cells; D062105:Molecular Docking Simulation; D009976:Orthomyxoviridae Infections / Q000188:drug therapy / Q000821:virology; D053978:Pentacyclic Triterpenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D053586:Virus Internalization / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D053978:Pentacyclic Triterpenes; D001205:Ascorbic Acid
keywords: Entry inhibitor; Hemagglutinin; Influenza virus; Pentacyclic triterpene; Sialic acid receptor; l-ascorbic acid