A Computationally Designed Inhibitor of an Epstein-Barr Viral Bcl-2 Protein Induces Apoptosis in Infected Cells
Abstract
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.
Recommended Citation
E. Procko and G. Y. Berguig and B. W. Shen and Y. Song and S. Frayo and A. J. Convertine and D. Margineantu and G. Booth and B. E. Correia and Y. Cheng and W. R. Schief and D. M. Hockenbery and O. W. Press and B. L. Stoddard and P. S. Stayton and D. Baker, "A Computationally Designed Inhibitor of an Epstein-Barr Viral Bcl-2 Protein Induces Apoptosis in Infected Cells," Cell, vol. 157, no. 7, pp. 1644 - 1656, Elsevier, Jun 2014.
The definitive version is available at https://doi.org/10.1016/j.cell.2014.04.034
Department(s)
Materials Science and Engineering
Keywords and Phrases
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
International Standard Serial Number (ISSN)
0092-8674
Document Type
Article - Journal
Document Version
Citation
File Type
text
Language(s)
English
Rights
© 2014 Elsevier, All rights reserved.
Publication Date
01 Jun 2014
PubMed ID
24949974
Comments
This work was supported by the National Institute of General Medical Studies of the National Institutes of Health (NIH) under award numbers P41GM103533 and R01GM49857; NIH grants R21EB014572, R01CA076287, and R01CA154897; the Washington State Life Sciences Discovery Fund grant 2496490 to the Center for Intracellular Delivery of Biologics; the Defence Threat Reduction Agency; and a grant by the David and Patricia Giuliani Family Foundation. Computational resources were provided by BOINC and supported by the National Science Foundation through awards SCI-0221529, SCI-0438443, SCI-0506411, PHY/0555655, and OCI-0721124.