A Computationally Designed Inhibitor of an Epstein-Barr Viral Bcl-2 Protein Induces Apoptosis in Infected Cells | Zendy

Erik Procko | Zendy; Geoffrey Y. Berguig | Zendy; Betty Shen | Zendy; Yifan Song | Zendy; Shani L. Frayo | Zendy; Anthony J. Convertine | Zendy; Daciana Margineantu | Zendy; Garrett C. Booth | Zendy; Bruno E. Correia | Zendy; Yuanhua Cheng | Zendy; William R. Schief | Zendy; David M. Hockenbery | Zendy; Oliver W. Press | Zendy; Barry Stoddard | Zendy; Patrick S. Stayton | Zendy; David Baker | Zendy

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A Computationally Designed Inhibitor of an Epstein-Barr Viral Bcl-2 Protein Induces Apoptosis in Infected Cells

Author(s) -

Erik Procko,

Geoffrey Y. Berguig,

Betty Shen,

Yifan Song,

Shani L. Frayo,

Anthony J. Convertine,

Daciana Margineantu,

Garrett C. Booth,

Bruno E. Correia,

Yuanhua Cheng,

William R. Schief,

David M. Hockenbery,

Oliver W. Press,

Barry Stoddard,

Patrick S. Stayton,

David Baker

Publication year - 2014

Publication title -

cell

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 26.304

H-Index - 776

eISSN - 1097-4172

pISSN - 0092-8674

DOI - 10.1016/j.cell.2014.04.034

Subject(s) - biology , apoptosis , antibody , virus , intracellular , epstein–barr virus , virology , cancer cell , gene , cell culture , cancer research , jurkat cells , cancer , microbiology and biotechnology , immunology , biochemistry , genetics , immune system , t cell

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.

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