title: Design and Structural Characterization of Potent and Selective Inhibitors of Phosphatidylinositol 4 Kinase IIIβ.
abstract: Type III phosphatidylinositol 4-kinase (PI4KIIIβ) is an essential enzyme in mediating membrane trafficking and is implicated in a variety of pathogenic processes. It is a key host factor mediating replication of RNA viruses. The design of potent and specific inhibitors of this enzyme will be essential to define its cellular roles and may lead to novel antiviral therapeutics. We previously reported the PI4K inhibitor PIK93, and this compound has defined key functions of PI4KIIIβ. However, this compound showed high cross reactivity with class I and III PI3Ks. Using structure-based drug design, we have designed novel potent and selective (>1000-fold over class I and class III PI3Ks) PI4KIIIβ inhibitors. These compounds showed antiviral activity against hepatitis C virus. The co-crystal structure of PI4KIIIβ bound to one of the most potent compounds reveals the molecular basis of specificity. This work will be vital in the design of novel PI4KIIIβ inhibitors, which may play significant roles as antiviral therapeutics.
authors.affiliation: Howard Hughes Medical Institute and Department of Cellular and Molecular Pharmacology, University of California, San Francisco (UCSF) , San Francisco, California 94143, United States.
authors.forename: Florentine U
authors.initials: FU
authors.lastname: Rutaganira
authors.affiliation: Department of Biochemistry and Microbiology, University of Victoria , Victoria, BC V8W 2Y2, Canada.
authors.forename: Melissa L
authors.initials: ML
authors.lastname: Fowler
authors.affiliation: Department of Biochemistry and Microbiology, University of Victoria , Victoria, BC V8W 2Y2, Canada.
authors.forename: Jacob A
authors.initials: JA
authors.lastname: McPhail
authors.affiliation: Department of Medicine and Department of Microbiology & Immunology, Stanford University , Palo Alto, California 94305, United States.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Gelman
authors.affiliation: Department of Medicine and Department of Microbiology & Immunology, Stanford University , Palo Alto, California 94305, United States.
authors.forename: Khanh
authors.initials: K
authors.lastname: Nguyen
authors.affiliation: Department of Medicine and Department of Microbiology & Immunology, Stanford University , Palo Alto, California 94305, United States.
authors.forename: Anming
authors.initials: A
authors.lastname: Xiong
authors.affiliation: Department of Biochemistry and Microbiology, University of Victoria , Victoria, BC V8W 2Y2, Canada.
authors.forename: Gillian L
authors.initials: GL
authors.lastname: Dornan
authors.affiliation: Howard Hughes Medical Institute and Department of Cellular and Molecular Pharmacology, University of California, San Francisco (UCSF) , San Francisco, California 94143, United States.
authors.forename: Brandon
authors.initials: B
authors.lastname: Tavshanjian
authors.affiliation: Department of Medicine and Department of Microbiology & Immunology, Stanford University , Palo Alto, California 94305, United States.|Veterans Administration Medical Center , Palo Alto, California 94304, United States.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Glenn
authors.affiliation: Howard Hughes Medical Institute and Department of Cellular and Molecular Pharmacology, University of California, San Francisco (UCSF) , San Francisco, California 94143, United States.
authors.forename: Kevan M
authors.initials: KM
authors.lastname: Shokat
authors.affiliation: Department of Biochemistry and Microbiology, University of Victoria , Victoria, BC V8W 2Y2, Canada.
authors.forename: John E
authors.initials: JE
authors.lastname: Burke
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D016174:Hepacivirus / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D015394:Molecular Structure; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D017853:Phosphotransferases (Alcohol Group Acceptor); D047428:Protein Kinase Inhibitors; C581087:PI4KB protein, human