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

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

Author information

1
Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.
2
Department of Bioengineering, University of Washington, Seattle, WA 98195, USA.
3
Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
4
The Scripps Research Institute, La Jolla, CA 92037, USA.
5
Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195, USA.
#
Contributed equally

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.

PMID:
24949974
PMCID:
PMC4079535
DOI:
10.1016/j.cell.2014.04.034
[Indexed for MEDLINE]
Free PMC Article
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