A Computationally Designed Inhibitor of an Epstein-Barr Viral Bcl-2 Protein Induces Apoptosis in Infected Cells
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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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Previous methods can scaffold functional sites made up of one or two contiguous chain segments.
“Previous methods can scaffold functional sites made up of one or two contiguous chain segments (6–10), but with the exception of helical bundles (8) these do not extend readily to more complex sites composed of three or more chain segments, and the generated backbones are not guaranteed to be designable (encodable by some amino acid sequence).”
From Scaffolding protein functional sites using deep learning (2022) · cites this paper as [6]
The backbones generated by previous functional-site scaffolding methods are not guaranteed to be designable.
“Previous methods can scaffold functional sites made up of one or two contiguous chain segments (6–10), but with the exception of helical bundles (8) these do not extend readily to more complex sites composed of three or more chain segments, and the generated backbones are not guaranteed to be designable (encodable by some amino acid sequence).”
From Scaffolding protein functional sites using deep learning (2022) · cites this paper as [6]
With the exception of helical bundles, previous methods do not extend readily to more complex functional sites composed of three or more chain segments.
“Previous methods can scaffold functional sites made up of one or two contiguous chain segments (6–10), but with the exception of helical bundles (8) these do not extend readily to more complex sites composed of three or more chain segments, and the generated backbones are not guaranteed to be designable (encodable by some amino acid sequence).”
From Scaffolding protein functional sites using deep learning (2022) · cites this paper as [6]
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Self-citation
- Authors
- Procko, E., Berguig, G. Y., Shen, B. W., Song, Y., Frayo, S., Convertine, A. J., Margineantu, D., Booth, G., Correia, B. E., Cheng, Y., Schief, W. R., Hockenbery, D. M., Press, O. W., Stoddard, B. L., Stayton, P. S., & Baker, D.
- Affiliations
- University of Washington (US)
- Fred Hutch Cancer Center (US)
- Scripps Research Institute (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Baker, David
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2014-06
- Volume
- 157
- Issue
- 7
- Pages
- 1644-1656
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC4079535
- OpenAlex
- W2057706355
- Cited by
- 127
- References
- 53
- Citations by year
- 2026: 5 · 2025: 4 · 2024: 3 · 2023: 7 · 2022: 12 · 2021: 13 · 2020: 13 · 2019: 8 · 2018: 13 · 2017: 19 · 2016: 12 · 2015: 13 · 2014: 5
- FWCI
- 6.70
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Howard Hughes Medical Institute
- National Cancer Institute (R01CA154897, R01CA076287)
- National Institute of General Medical Sciences (R01GM049857, P41GM103533, R01-GM49857)
- National Institute of Biomedical Imaging and Bioengineering (R21EB014572)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
- Health Sciences › Medicine › Oncology › Viral-associated cancers and disorders
- Keywords
- Epstein-Barr virus, BHRF1, Bcl-2 homolog, bindi, apoptosis induction, viral evasion of apoptosis, EBV-associated lymphoma, tumor suppression, xenograft models, antibody-drug conjugates
- MeSH terms
- Amino Acid Sequence, Animals, Herpesvirus 4, Human, Humans, Models, Molecular, Molecular Sequence Data, Neoplasm Transplantation, Proteins, Viral Proteins, Protein Engineering, Lymphoma, B-Cell, Sequence Alignment, Apoptosis, Crystallography, X-Ray, Computational Biology, Epstein-Barr Virus Infections, Mice, Heterografts
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