Designed BH3 Peptides with High Affinity and Specificity for Targeting Mcl-1 in Cells
Author(s)
Ryan, Jeremy A.; Letai, Anthony; Foight, Glenna W.; Gulla, Stefano V.; Keating, Amy E.
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Mcl-1 is overexpressed in many cancers and can confer resistance to cell-death signaling in refractory disease. Molecules that specifically inhibit Mcl-1 hold potential for diagnosing and disrupting Mcl-1-dependent cell survival. We selected three peptides from a yeast-surface display library that showed moderate specificity and affinity for binding to Mcl-1 over Bfl-1, Bcl-x[subscript L], Bcl-2, and Bcl-w. Specificity for Mcl-1 was improved by introducing threonine at peptide position 2e. The most specific peptide, MS1, bound Mcl-1 with 40-fold or greater specificity over four other human Bcl-2 paralogs. In BH3 profiling assays, MS1 caused depolarization in several human Mcl-1-dependent cell lines with EC[subscript 50] values of ∼3 μM, contrasted with EC[subscript 50] values of >100 μM for Bcl-2-, Bcl-xL-, or Bfl-1-dependent cell lines. MS1 is at least 30-fold more potent in this assay than the previously used Mcl-1 targeting reagent NoxaA BH3. These peptides can be used to detect Mcl-1 dependency in cells and provide leads for developing Mcl-1 targeting therapeutics.
Date issued
2014-07Department
Massachusetts Institute of Technology. Department of BiologyJournal
ACS Chemical Biology
Publisher
American Chemical Society (ACS)
Citation
Foight, Glenna Wink et al. “Designed BH3 Peptides with High Affinity and Specificity for Targeting Mcl-1 in Cells.” ACS Chemical Biology 9.9 (2014): 1962–1968.
Version: Final published version
ISSN
1554-8929
1554-8937