Novel Peptidic Agents for Targeting Chemoresistant Anti-Apoptotic Bfl-1
Peptide inhibitors of Bfl-1, an anti-apoptotic protein, allow for selective targeting of Bfl-1 dependent cancer cells in therapeutic treatment. Selective peptides may also be used as Bfl-1-detection reagents. This allows for cellular profiling for anti-apoptotic protein dependency, thus potentially acting as a diagnostic tool for stratifying patients.
Researchers
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selective bfl-1 peptides
United States of America | Granted | 11,198,715
Figures
The BH3 profiling assay detects MOMP by monitoring JC-1 fluorescence in permeabilized cells treated with different peptides. Graphs demonstrating the BH3 profiling of FS2 with BCR-ABL-expressing B-lineage acute lymphoblastic leukemia (B-ALL) cell lines. Error bars indicate the standard deviation over 3 or more replicates.
(A) X-ray structure of Bfl-1 covalently cross-linked to an electrophilic variant of a Bfl-1 selective peptide. (B) Electron density map of covalent crosslink between peptide and Bfl-1. Figure adapted from Jenson et al., Elife 2017.
Image of a covalent binding assay.
The BH3 profiling assay detects MOMP by monitoring JC-1 fluorescence in permeabilized cells treated with different peptides. Graphs of the BH3 profiling of FS2gX. Error bars indicate the standard deviation over 3 or more replicates
Cytochrome c release induced by designed peptides in four cell lines that depend on ectopic expression of Mcl-1, Bcl-2, Bcl-xL or Bfl-1 for survival.
Technology
Selective peptide inhibitors of Bfl-1 were identified by screening for sequence variants of the BH3 motif of PUMA, a highly potent binder of Bcl-2 family members. Peptides were designed using computational analysis followed by experimental screening that identified peptides with high affinity for Bfl-1 yet weakened interactions with other anti-apoptotic proteins. The lead peptide inhibitors are >100-fold selective for binding to Bfl-1 binding over other anti-apoptotic proteins of Bcl-2 family. Selectivity towards Bfl-1 was further augmented by modifying the peptide inhibitors with electrophiles to allow for covalent interaction in the binding pocket of Bfl-1. The selectivity of the peptide Bfl-1 inhibitors in a cellular context was confirmed by the relative mitochondrial depolarization or cytochrome-c release after peptide treatment of Bfl-1 dependent cells vs. other anti-apoptotic protein dependent cells.
Problem Addressed
Many cancer cells overexpress anti-apoptotic Bcl-2 family proteins that confer resistance to chemotherapy treatment. Selective inhibitors of Bcl-2 are available in clinic to treat Bcl-2 dependent cancers. However, such tools are missing for Bfl-1. Selective inhibitors allow for selective targeting of Bfl-1 dependent cancer cells while limiting systemic toxicity.
Advantages
- The peptide inhibitors are potent and selective towards Bfl-1 with >100-fold selectivity over other anti-apoptotic proteins
- The peptide inhibitors can also be used as diagnostic tools to profile cells for Bfl-1 dependency
Publications
Jenson, J. M., et al. "Epistatic mutations in PUMA BH3 drive an alternate binding mode to potently and selectively inhibit anti-apoptotic Bfl-1." eLife 6 (2017): e25541. https://doi.org/10.7554/eLife.25541.
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