title: A Conserved Inhibitory Mechanism of a Lycorine Derivative against Enterovirus and Hepatitis C Virus.
abstract: Enterovirus 71 (EV71) (Picornaviridae family) and hepatitis C virus (HCV) (Flaviviridae family) are the causative agents of human hand, foot, and mouth disease (HFMD) and hepatitis C, resulting in a severe pandemic involving millions of infections in the Asia-Pacific region and worldwide. The great impact of EV71 and HCV on public health highlights the need to further our understanding of the biology of these two viruses and develop effective therapeutic antivirals. Here, we evaluated a total of 32 lycorine derivatives and demonstrated that 1-acetyllycorine suppressed the proliferation of multiple strains of EV71 in various cells. The results of the drug resistance analysis revealed that 1-acetyllycorine targeted a phenylalanine (F76) in EV71 2A protease (2A(pro)) to stabilize the conformation of a unique zinc finger. Most interestingly, the zinc binding site in EV71 2A(pro) is the exclusive homolog of HCV NS3 among all viruses. Further analysis revealed that 1-acetyllycorine also inhibits HCV with high efficacy, and the mutation on R118 in HCV NS3, which corresponds to F76 in EV71 2A(pro), confers the resistance of HCV to 1-acetyllycorine. These results revealed a conserved mechanism of 1-acetyllycorine against EV71 and HCV through targeting viral proteases. We also documented the significant synergistic anti-EV71 and anti-HCV effects of 1-acetyllycorine with reported inhibitors, supporting potential combination therapy for the treatment of EV71 and HCV infections.
authors.affiliation: College of Pharmacy and State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Guo
authors.affiliation: College of Pharmacy and State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, China Collaborative Innovation Center for Biotherapy, Tsinghua University, Beijing, China.
authors.forename: Yaxin
authors.initials: Y
authors.lastname: Wang
authors.affiliation: College of Pharmacy and State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, China Collaborative Innovation Center for Biotherapy, Tsinghua University, Beijing, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Cao
authors.affiliation: College of Pharmacy and State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Wang
authors.affiliation: Tsinghua-Peking Center for Life Sciences, MOE Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology, Department of Chemistry, Tsinghua University, Beijing, China School of Medicine, Tsinghua University, Beijing, China Collaborative Innovation Center for Biotherapy, Tsinghua University, Beijing, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Qing
authors.affiliation: Department of Chemistry, Tsinghua University, Beijing, China.
authors.forename: Qizhen
authors.initials: Q
authors.lastname: Zheng
authors.affiliation: College of Pharmacy and State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, China.
authors.forename: Luqing
authors.initials: L
authors.lastname: Shang
authors.affiliation: College of Pharmacy and State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, China zheng_yin@nankai.edu.cn sunyn@moon.ibp.ac.cn.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Yin
authors.affiliation: National Laboratory of Macromolecules, Institute of Biophysics, Chinese Academy of Science, Beijing, China zheng_yin@nankai.edu.cn sunyn@moon.ibp.ac.cn.
authors.forename: Yuna
authors.initials: Y
authors.lastname: Sun
mesh_terms: D047151:Amaryllidaceae Alkaloids / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D004347:Drug Interactions; D024882:Drug Resistance, Viral / Q000187:drug effects / Q000235:genetics*; D029821:Enterovirus A, Human / Q000187:drug effects* / Q000235:genetics; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D009154:Mutation; D010617:Phenanthridines / Q000737:chemistry* / Q000494:pharmacology; D040681:Structural Homology, Protein; D017361:Viral Nonstructural Proteins / Q000737:chemistry; D014779:Virus Replication / Q000187:drug effects; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D047151:Amaryllidaceae Alkaloids; D000998:Antiviral Agents; D010617:Phenanthridines; D017361:Viral Nonstructural Proteins; C000611892:1-acetyllycorine; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C015330:lycorine