Designed BH3 Peptides with High Affinity and Specificity for Targeting Mcl-1 in Cells
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Keating_Designed BH3.pdf
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Author(s)
Ryan, Jeremy A.
Letai, Anthony
Foight, Glenna W.
Gulla, Stefano V.
Keating, Amy E.
Date Issued
July 2014
Journal
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
Abstract
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.
MIT Department
Massachusetts Institute of Technology. Department of Biology
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Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use.
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DOI of Published Version
https://doi.org/10.1021/cb500340w
