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.
- BH3 protein,
- BIM protein,
- bortezomib,
- copolymer,
- cyclophosphamide,
- cytochrome c,
- epitope,
- proline,
- protein bcl 2,
- BHRF1 protein,
- protein bcl 2,
- unclassified drug,
- virus protein, animal experiment,
- animal model,
- animal tissue,
- apoptosis,
- article,
- B cell lymphoma,
- BHRF1 gene,
- bindi gene,
- binding affinity,
- cancer inhibition,
- cancer survival,
- codon,
- controlled study,
- crystal structure,
- Epstein Barr virus,
- Escherichia coli,
- fluorescence activated cell sorting,
- gel permeation chromatography,
- hydrophobicity,
- ligand binding,
- micelle,
- mouse,
- mutagenesis,
- nonhuman,
- polymerase chain reaction,
- priority journal,
- protein binding,
- protein expression,
- protein motif,
- protein protein interaction,
- protein purification,
- protein secondary structure,
- protein stability,
- side chain grafting,
- site directed mutagenesis,
- target cell,
- tumor volume,
- virus gene,
- yeast,
- apoptosis,
- Article,
- cell survival,
- computer aided design,
- Epstein Barr virus,
- Epstein Barr virus infection,
- human,
- human cell,
- laboratory,
- protein function,
- protein interaction,
- protein structure,
- tumor growth,
- xenograft, Amino Acid Sequence,
- Animals,
- Apoptosis,
- Computational Biology,
- Crystallography, X-Ray,
- Epstein-Barr Virus Infections,
- Herpesvirus 4, Human,
- Heterografts,
- Humans,
- Lymphoma, B-Cell,
- Mice,
- Models, Molecular,
- Molecular Sequence Data,
- Neoplasm Transplantation,
- Protein Engineering,
- Proteins,
- Sequence Alignment,
- Viral Proteins
Available at: http://works.bepress.com/anthony-convertine/1/