title: Design and Synthesis of Cajanine Analogues against Hepatitis C Virus through Down-Regulating Host Chondroitin Sulfate N-Acetylgalactosaminyltransferase 1.
abstract: There still remains a need to develop new anti-HCV agents with distinct mechanism of action (MOA) due to the occurrence of resistance to direct-acting antiviral agents (DAAs). Cajanine, a stilbenic component isolated from Cajanus cajan L., was identified as a potent HCV inhibitor by phenotypic screening in this work (EC50= 3.17 ± 0.75 μM). The intensive structure optimization provided significant insights into the structure-activity relationships. Furthermore, the MOA study revealed that cajanine inhibited HCV replications via down-regulating a cellular protein chondroitin sulfate N-acetylgalactosaminyltransferase 1. In consistency with this host-targeting mechanism, cajanine showed the similar magnitude of inhibitory activity against both drug-resistant and wild-type HCV and synergistically inhibited HCV replication with approved DAAs. Taken together, our study not only presented cajanine derivatives as a novel class of anti-HCV agents but also discovered a promising anti-HCV target to combat drug resistance.
authors: Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College , No. 1, Tiantan Xili, Beijing 100050, China.
authors: Xing-Yue
authors: XY
authors: Ji
authors: Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College , No. 1, Tiantan Xili, Beijing 100050, China.
authors: Jin-Hua
authors: JH
authors: Chen
authors: Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College , No. 1, Tiantan Xili, Beijing 100050, China.
authors: Guang-Hui
authors: GH
authors: Zheng
authors: Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College , No. 1, Tiantan Xili, Beijing 100050, China.
authors: Meng-Hao
authors: MH
authors: Huang
authors: Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College , No. 1, Tiantan Xili, Beijing 100050, China.
authors: Lei
authors: L
authors: Zhang
authors: Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College , No. 1, Tiantan Xili, Beijing 100050, China.
authors: Hong
authors: H
authors: Yi
authors: Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College , No. 1, Tiantan Xili, Beijing 100050, China.
authors: Jie
authors: J
authors: Jin
authors: Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College , No. 1, Tiantan Xili, Beijing 100050, China.
authors: Jian-Dong
authors: JD
authors: Jiang
authors: Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College , No. 1, Tiantan Xili, Beijing 100050, China.
authors: Zong-Gen
authors: ZG
authors: Peng
authors: Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College , No. 1, Tiantan Xili, Beijing 100050, China.
authors: Zhuo-Rong
authors: ZR
authors: Li
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004054:Diethylstilbestrol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D016174:Hepacivirus / Q000187:drug effects*; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D017350:N-Acetylgalactosaminyltransferases / Q000096:biosynthesis* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000998:Antiviral Agents; D004791:Enzyme Inhibitors; C541583:cajanine; D004054:Diethylstilbestrol; D017350:N-Acetylgalactosaminyltransferases; C472559:chondroitin sulfate N-acetylgalactosaminyltransferase-1