Targeting the lateral interactions of transmembrane domain 5 of Epstein–Barr virus latent membrane protein 1

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.

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► Propose a cell based screen strategy for identifying TMDs disruptors
► Identified an LMP-1 TMD-5 self association disruptor, NSC 259242
► NSC 259242 disrupts TMD-5 homotrimerization and inhibits LMP-1 signaling