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 (#406)

Sofia Caria 1 , Srishti Chugh 1 , Duong Nhu 2 3 , Guillaume Lessene 2 3 , Marc Kvansakul 1
  1. La Trobe University, Bundoora, Melbourne, VIC, Australia
  2. The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
  3. The University of Melbourne, Parkville, Victoria, Australia

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

Epstein-Barr virus (EBV), a member of the γ-herpesviruses, infects the epithelium of the oropharynx and resting B cells. Acute infection manifests as infectious mononucleosis or glandular fever, whereas 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 have shown that BHRF1 interacts with these BH3-only proteins in a manner similar to its mammalian counterparts3 . Structure-based mutagenesis demonstrated that BHRF1 can prevent Bak activation by direct interaction, but prevents Bax activation indirectly by sequestering the BH3-only proteins Bim, Puma and tBid. 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 . Given the importance of BHRF1 in EBV-associated malignancies and in certain Burkitt lymphomas, the development of therapeutic inhibitors may be highly relevant for improved treatments. 

The available structural data formed the basis for the design of peptido-mimetics that target the BH3-ligand binding site of BHRF1. Several peptido-mimetics were designed, and their binding affinity determined through biosensor assays. The structure determination of BHRF1 in complex with such a peptido-mimetic 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).