Repositioning Antimicrobial Agent Pentamidine as a Disruptor of the Lateral Interactions of Transmembrane Domain 5 of EBV Latent Membrane Protein 1Reportar como inadecuado




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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.



Autor: Xiaohui Wang, Zeno Fiorini, Christina Smith, Yingning Zhang, Jing Li , Linda R. Watkins, Hang Yin

Fuente: http://plos.srce.hr/



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