A computationally designed inhibitor of an Epstein-Barr viral Bcl-2 protein induces apoptosis in infected cells

Cell. 2014 Jun 19;157(7):1644-1656. doi: 10.1016/j.cell.2014.04.034.


Because apoptosis of infected cells can limit virus production and spread, some viruses have co-opted prosurvival genes from the host. This includes the Epstein-Barr virus (EBV) gene BHRF1, a homolog of human Bcl-2 proteins that block apoptosis and are associated with cancer. Computational design and experimental optimization were used to generate a novel protein called BINDI that binds BHRF1 with picomolar affinity. BINDI recognizes the hydrophobic cleft of BHRF1 in a manner similar to other Bcl-2 protein interactions but makes many additional contacts to achieve exceptional affinity and specificity. BINDI induces apoptosis in EBV-infected cancer lines, and when delivered with an antibody-targeted intracellular delivery carrier, BINDI suppressed tumor growth and extended survival in a xenograft disease model of EBV-positive human lymphoma. High-specificity-designed proteins that selectively kill target cells may provide an advantage over the toxic compounds used in current generation antibody-drug conjugates.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Apoptosis / drug effects
  • Computational Biology
  • Crystallography, X-Ray
  • Epstein-Barr Virus Infections / drug therapy
  • Herpesvirus 4, Human / chemistry*
  • Herpesvirus 4, Human / physiology
  • Heterografts
  • Humans
  • Lymphoma, B-Cell / drug therapy
  • Mice
  • Models, Molecular
  • Molecular Sequence Data
  • Neoplasm Transplantation
  • Protein Engineering*
  • Proteins / chemistry
  • Proteins / metabolism
  • Proteins / pharmacology*
  • Sequence Alignment
  • Viral Proteins / antagonists & inhibitors*
  • Viral Proteins / chemistry


  • BHRF1 protein, Human herpesvirus 4
  • BINDI protein
  • Proteins
  • Viral Proteins

Associated data

  • PDB/4OYD