repositioning antimicrobial agent pentamidine as a disruptor of the lateral interactions of transmembrane domain 5 of ebv latent membrane protein 1重新定位抗菌剂喷他脒粉碎机的跨膜域的横向互动5 eb病毒潜伏膜蛋白1.pdfVIP

Repositioning Antimicrobial Agent Pentamidine as a Disruptor of the Lateral Interactions of Transmembrane Domain 5 of EBV Latent Membrane Protein 1 1,2 1 1 2 3 2 Xiaohui Wang , Zeno Fiorini , Christina Smith , Yingning Zhang , Jing Li *, Linda R. Watkins , Hang Yin1* 1 Department of Chemistry and Biochemistry and BioFrontiers Institute, University of Colorado at Boulder, Boulder, Colorado, United States of America, 2 Department of Psychology and Neuroscience, and the Center for Neuroscience, University of Colorado at Boulder, Boulder, Colorado, United States of America, 3 Department of Rheumatology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, People’s Republic of China 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) 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