title: Targeting the lateral interactions of transmembrane domain 5 of Epstein-Barr virus latent membrane protein 1.
abstract: The lateral transmembrane protein-protein interaction has been regarded as "undruggable" despite its importance in many 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 report a small molecule agent, NSC 259242 (compound 1), to be a TMD-5 self-association disruptor. Both the positively charged acetimidamide functional groups and the stilbene backbone of compound 1 are essential for its inhibitory activity. Furthermore, cell-based assays revealed that compound 1 inhibits full-length LMP-1 signaling in EBV infected B cells. These studies demonstrated a new strategy for identifying small molecule disruptors for investigating transmembrane protein-protein interactions.
authors.affiliation: Department of Chemistry and Biochemistry and Biofrontiers Institute, University of Colorado, Boulder, CO 80309-0596, USA.
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Wang
authors.forename: Jonel P
authors.initials: JP
authors.lastname: Saludes
authors.forename: Tina X
authors.initials: TX
authors.lastname: Zhao
authors.forename: Adam
authors.initials: A
authors.lastname: Csakai
authors.forename: Zeno
authors.initials: Z
authors.lastname: Fiorini
authors.forename: Sherry A
authors.initials: SA
authors.lastname: Chavez
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.forename: Gui-in
authors.initials: GI
authors.lastname: Lee
authors.forename: Krisztina
authors.initials: K
authors.lastname: Varga
authors.forename: Hang
authors.initials: H
authors.lastname: Yin
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004854:Herpesvirus 4, Human / Q000378:metabolism*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D008954:Models, Biological; D008956:Models, Chemical; D008958:Models, Molecular; D015233:Models, Statistical; D008968:Molecular Conformation; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000737:chemistry; D010455:Peptides / Q000737:chemistry; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D015398:Signal Transduction; D013050:Spectrometry, Fluorescence / Q000379:methods; D013266:Stilbamidines / Q000737:chemistry / Q000494:pharmacology*; D014763:Viral Matrix Proteins / Q000737:chemistry*
chemical_list: D000998:Antiviral Agents; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D016328:NF-kappa B; D010455:Peptides; D013266:Stilbamidines; D014763:Viral Matrix Proteins; D009569:Nitric Oxide; C034719:2-hydroxystilbamidine isethionate