title: Cyclopiazonic acid, an inhibitor of calcium-dependent ATPases with antiviral activity against human respiratory syncytial virus.
abstract: Human respiratory syncytial virus (RSV) is a common cause of lower respiratory tract infections in infants and young children worldwide, yet no vaccine or effective antiviral treatment is available. To search for new anti-RSV agents, we developed a cell-based assay that measures inhibition of RSV-induced cytopathic effect (CPE) and identified cyclopiazonic acid (CPA), an intracellular calcium ATPase inhibitor as a RSV inhibitor (EC50 values 4.13 μM) by screening of natural product library. CPA inhibited the replication of RSV strains belonging to both A and B subgroups and human parainfluenza virus type 3, but not Enterovirus 71. Mechanism of action study by time-of-addition assay and minigenome assay revealed that CPA acts at the step of virus genome replication and/or transcription. Moreover, two other calcium ATPase inhibitors (Thapsigargin and BHQ) and calcium ionophores (A23187 and ionomycin), but not calcium channel blockers (nifedipine, nimodipine, and tetrandrine), also had similar effect. These results indicate that an increase in intracellular calcium concentration is detrimental to RSV replication. Thus, our findings provide a new strategy for anti-RSV therapy via increasing intracellular calcium concentration.
authors.affiliation: School of Life Sciences, Shanghai University, Shanghai, 200444, China; Pathogen Diagnostic Center, Key Laboratory of Molecular Virology & Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, 200031, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Cui
authors.affiliation: Pathogen Diagnostic Center, Key Laboratory of Molecular Virology & Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, 200031, China.
authors.forename: Yizhuo
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Pathogen Diagnostic Center, Key Laboratory of Molecular Virology & Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, 200031, China.
authors.forename: Liu
authors.initials: L
authors.lastname: Wang
authors.affiliation: School of Life Sciences, Shanghai University, Shanghai, 200444, China; Pathogen Diagnostic Center, Key Laboratory of Molecular Virology & Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, 200031, China.
authors.forename: Guiming
authors.initials: G
authors.lastname: Li
authors.affiliation: Pathogen Diagnostic Center, Key Laboratory of Molecular Virology & Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, 200031, China.
authors.forename: Ke
authors.initials: K
authors.lastname: Lan
authors.affiliation: Pathogen Diagnostic Center, Key Laboratory of Molecular Virology & Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, 200031, China; Shandong University-Helmholtz Institute of Biotechnology, Shandong University, Qingdao, 266101, China. Electronic address: altmeyer@sdu.edu.cn.
authors.forename: Ralf
authors.initials: R
authors.lastname: Altmeyer
authors.affiliation: Pathogen Diagnostic Center, Key Laboratory of Molecular Virology & Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, 200031, China. Electronic address: gangzou@ips.ac.cn.
authors.forename: Gang
authors.initials: G
authors.lastname: Zou
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D001688:Biological Products / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D000252:Calcium-Transporting ATPases / Q000037:antagonists & inhibitors*; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D015967:Gene Expression Regulation, Viral / Q000187:drug effects; D057166:High-Throughput Screening Assays; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology*; D018357:Respiratory Syncytial Virus Infections / Q000378:metabolism / Q000821:virology; D018113:Respiratory Syncytial Virus, Human / Q000187:drug effects* / Q000502:physiology*; D054852:Small Molecule Libraries; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D001688:Biological Products; D007211:Indoles; D054852:Small Molecule Libraries; D000252:Calcium-Transporting ATPases; D000254:Sodium-Potassium-Exchanging ATPase; D002118:Calcium; C000543:cyclopiazonic acid
keywords: Calcium ATPases; Cyclopiazonic acid; High-throughput screening; Natural product; Respiratory syncytial virus