BHRF1 inhibition with peptidomimetics — ASN Events
  1. Schedule
  2. Session Twelve - Poster Session D including Happy Hour & Trade Display
  3. BHRF1 inhibition with peptidomimetics

BHRF1 inhibition with peptidomimetics (#411)

Sofia Caria 1 , Duong Nhu 2 , Srishti Chugh 1 , Guillaume Lessene 2 , Marc Kvansakul 1
  1. La Trobe University, Bundoora, VIC, Australia
  2. The Walter and Eliza Hall Institute of Medical Research, Bundoora, VIC, Australia

Viruses overcome host apoptotic defences to ensure their own survival. Despite the complexity of mammalian cell death processes, viruses have evolved mechanisms for subverting the apoptotic machinery, which includes homologs of the mammalian prosurvival protein Bcl-21.

Epstein-Barr virus (EBV), γ-herpesviruses family member, infects the epithelium of the oropharynx and resting B cells. Chronic EBV-associated transformation is associated with Burkitt’s lymphoma, Hodgkin’s disease and nasopharyngeal carcinoma2.

EBV BHRF1 is a sequence, structural and functional homologue of Bcl-2. It has been shown that BHRF1 is a potent inhibitor of apoptosis, and confers chemoresistance in mouse lymphoma models similar to mammalian Bcl-23.

The crystal structures of BHRF1 in complex with Bim and Bak BH3 peptides shown that BHRF1 interacts with these BH3-only proteins in a manner similar to its mammalian counterparts3. Unlike mammalian pro-survival proteins, BHRF1 does not interact with the selective/sensitizer BH3-only proteins3.

BHRF1 interactions with pro-apoptotic Bcl-2 proteins resemble the ones verified in mammalian pro-survival proteins such as Bcl-xL3. The available structural data formed the basis for the design of peptidomimetics that target the BH3-ligand binding site of BHRF1. Several peptidomimetics were designed, and their binding affinity determined through biosensor assays. The structure determination of BHRF1•WEHI-271 complex has enabled us to study in detail the interactions required for ligand binding to BHRF1, and to design improvements to the compound for higher binding affinity. Ultimately this may lead to a possible clinically relevant inhibitor of BHRF1.

  1. L. Galluzzi, C. Brenner, E. Morselli, Z. Touat and G. Kroemer PLoS Pathog. 4, e1000018, (2008)
  2. D. H. Crawford Philos Trans R. Soc. Lond. B Biol. Sci. 356, 461 (2001)
  3. M. Kvansakul, A. H. Wei, J. I. Fletcher, S. N. Willis, L. Chen, A. W. Roberts, D. C. S. Huang and P. M. Colman PLoS Pathog. 6, e1001236 (2010)