title: Repositioning antimicrobial agent pentamidine as a disruptor of the lateral interactions of transmembrane domain 5 of EBV latent membrane protein 1.
abstract: The lateral transmembrane protein-protein interactions (PPI) have been regarded as "undruggable" despite their importance in many essential biological processes. The homo-trimerization of transmembrane domain 5 (TMD-5) of latent membrane protein 1 (LMP-1) is critical for the constitutive oncogenic activation of the Epstein-Barr virus (EBV). Herein we repurpose the antimicrobial agent pentamidine as a regulator of LMP-1 TMD-5 lateral interactions. The results of ToxR assay, tryptophan fluorescence assay, courmarin fluorescence dequenching assay, and Bis-Tris sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) consistently show pentamidine disrupts LMP-1 TMD-5 lateral interactions. Furthermore, pentamidine inhibits LMP-1 signaling, inducing cellular apoptosis and suppressing cell proliferation in the EBV infected B cells. In contrast, EBV negative cells are less susceptible to pentamidine. This study provides a novel non-peptide small molecule agent for regulating LMP-1 TMD-5 lateral interactions.
authors.affiliation: Department of Chemistry and Biochemistry and BioFrontiers Institute, University of Colorado at Boulder, Boulder, Colorado, United States of America.
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Wang
authors.forename: Zeno
authors.initials: Z
authors.lastname: Fiorini
authors.forename: Christina
authors.initials: C
authors.lastname: Smith
authors.forename: Yingning
authors.initials: Y
authors.lastname: Zhang
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.forename: Linda R
authors.initials: LR
authors.lastname: Watkins
authors.forename: Hang
authors.initials: H
authors.lastname: Yin
mesh_terms: D000890:Anti-Infective Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001402:B-Lymphocytes / Q000187:drug effects / Q000821:virology*; D001426:Bacterial Proteins / Q000235:genetics; D001681:Biological Assay; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000235:genetics; D004591:Electrophoresis, Polyacrylamide Gel; D005456:Fluorescent Dyes; D004854:Herpesvirus 4, Human / Q000737:chemistry* / Q000187:drug effects* / Q000502:physiology; D054884:Host-Pathogen Interactions; D006801:Humans; D010419:Pentamidine / Q000494:pharmacology*; D010957:Plasmids; D055503:Protein Multimerization / Q000187:drug effects; D017434:Protein Structure, Tertiary; D015398:Signal Transduction / Q000187:drug effects; D014157:Transcription Factors / Q000235:genetics; D014763:Viral Matrix Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D014775:Virus Activation / Q000187:drug effects
chemical_list: D000890:Anti-Infective Agents; D001426:Bacterial Proteins; D004268:DNA-Binding Proteins; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D005456:Fluorescent Dyes; D014157:Transcription Factors; D014763:Viral Matrix Proteins; C066719:toxR protein, bacteria; D010419:Pentamidine