title: 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.
authors.affiliation: Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.
authors.forename: Erik
authors.initials: E
authors.lastname: Procko
authors.affiliation: Department of Bioengineering, University of Washington, Seattle, WA 98195, USA.
authors.forename: Geoffrey Y
authors.initials: GY
authors.lastname: Berguig
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
authors.forename: Betty W
authors.initials: BW
authors.lastname: Shen
authors.affiliation: Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.
authors.forename: Yifan
authors.initials: Y
authors.lastname: Song
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
authors.forename: Shani
authors.initials: S
authors.lastname: Frayo
authors.affiliation: Department of Bioengineering, University of Washington, Seattle, WA 98195, USA.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Convertine
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
authors.forename: Daciana
authors.initials: D
authors.lastname: Margineantu
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
authors.forename: Garrett
authors.initials: G
authors.lastname: Booth
authors.affiliation: The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Bruno E
authors.initials: BE
authors.lastname: Correia
authors.affiliation: Department of Bioengineering, University of Washington, Seattle, WA 98195, USA.
authors.forename: Yuanhua
authors.initials: Y
authors.lastname: Cheng
authors.affiliation: The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: William R
authors.initials: WR
authors.lastname: Schief
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Hockenbery
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
authors.forename: Oliver W
authors.initials: OW
authors.lastname: Press
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
authors.forename: Barry L
authors.initials: BL
authors.lastname: Stoddard
authors.affiliation: Department of Bioengineering, University of Washington, Seattle, WA 98195, USA.
authors.forename: Patrick S
authors.initials: PS
authors.lastname: Stayton
authors.affiliation: Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.|Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195, USA.
authors.forename: David
authors.initials: D
authors.lastname: Baker
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D019295:Computational Biology; D018360:Crystallography, X-Ray; D020031:Epstein-Barr Virus Infections / Q000188:drug therapy; D004854:Herpesvirus 4, Human / Q000737:chemistry* / Q000502:physiology; D064593:Heterografts; D006801:Humans; D016393:Lymphoma, B-Cell / Q000188:drug therapy; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009368:Neoplasm Transplantation; D015202:Protein Engineering; D011506:Proteins / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D016415:Sequence Alignment; D014764:Viral Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry
chemical_list: C083278:BHRF1 protein, Human herpesvirus 4; C000591254:BINDI protein; D011506:Proteins; D014764:Viral Proteins