title: Novel Chemical Ligands to Ebola Virus and Marburg Virus Nucleoproteins Identified by Combining Affinity Mass Spectrometry and Metabolomics Approaches.
abstract: The nucleoprotein (NP) of Ebola virus (EBOV) and Marburg virus (MARV) is an essential component of the viral ribonucleoprotein complex and significantly impacts replication and transcription of the viral RNA genome. Although NP is regarded as a promising antiviral druggable target, no chemical ligands have been reported to interact with EBOV NP or MARV NP. We identified two compounds from a traditional Chinese medicine Gancao (licorice root) that can bind both NPs by combining affinity mass spectrometry and metabolomics approaches. These two ligands, 18β-glycyrrhetinic acid and licochalcone A, were verified by defined compound mixture screens and further characterized with individual ligand binding assays. Accompanying biophysical analyses demonstrate that binding of 18β-glycyrrhetinic acid to EBOV NP significantly reduces protein thermal stability, induces formation of large NP oligomers, and disrupts the critical association of viral ssRNA with NP complexes whereas the compound showed no such activity on MARV NP. Our study has revealed the substantial potential of new analytical techniques in ligand discovery from natural herb resources. In addition, identification of a chemical ligand that influences the oligomeric state and RNA-binding function of EBOV NP sheds new light on antiviral drug development.
authors.affiliation: College of Biotechnology, Tianjin University of Science &Technology, Tianjin 300457, China.|High-throughput Molecular Drug Discovery Center, Tianjin Joint Academy of Biotechnology and Medicine, Tianjin 300457, China.
authors.forename: Xu
authors.initials: X
authors.lastname: Fu
authors.affiliation: High-throughput Molecular Drug Discovery Center, Tianjin Joint Academy of Biotechnology and Medicine, Tianjin 300457, China.|College of Pharmacy, Nankai University, Tianjin 300071, China.
authors.forename: Zhihua
authors.initials: Z
authors.lastname: Wang
authors.affiliation: High-throughput Molecular Drug Discovery Center, Tianjin Joint Academy of Biotechnology and Medicine, Tianjin 300457, China.
authors.forename: Lixin
authors.initials: L
authors.lastname: Li
authors.affiliation: High-throughput Molecular Drug Discovery Center, Tianjin Joint Academy of Biotechnology and Medicine, Tianjin 300457, China.
authors.forename: Shishang
authors.initials: S
authors.lastname: Dong
authors.affiliation: Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, Tianjin 300308, China.
authors.forename: Zhucui
authors.initials: Z
authors.lastname: Li
authors.affiliation: Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China.
authors.forename: Zhenzuo
authors.initials: Z
authors.lastname: Jiang
authors.affiliation: Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China.
authors.forename: Yuefei
authors.initials: Y
authors.lastname: Wang
authors.affiliation: iHuman Institute, ShanghaiTech University, Shanghai 201210, China.
authors.forename: Wenqing
authors.initials: W
authors.lastname: Shui
mesh_terms: D047188:Chalcones / Q000737:chemistry / Q000494:pharmacology*; D004365:Drugs, Chinese Herbal / Q000737:chemistry / Q000494:pharmacology; D029043:Ebolavirus / Q000378:metabolism*; D006034:Glycyrrhetinic Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D006035:Glycyrrhiza / Q000737:chemistry*; D008024:Ligands; D029024:Marburgvirus / Q000378:metabolism*; D013058:Mass Spectrometry; D055432:Metabolomics; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding / Q000187:drug effects; D055550:Protein Stability / Q000187:drug effects; D012367:RNA, Viral / Q000378:metabolism; D012261:Ribonucleoproteins / Q000737:chemistry / Q000378:metabolism*; D014764:Viral Proteins / Q000378:metabolism
chemical_list: D047188:Chalcones; D004365:Drugs, Chinese Herbal; D008024:Ligands; D012367:RNA, Viral; D012261:Ribonucleoproteins; D014764:Viral Proteins; C119129:18alpha-glycyrrhetinic acid; C070840:licochalcone A; D006034:Glycyrrhetinic Acid