Designed BH3 Peptides with High Affinity and Specificity for Targeting Mcl-1 in Cells
Citation
Foight, Glenna Wink, Jeremy A. Ryan, Stefano V. Gullá, Anthony Letai, and Amy E. Keating. 2014. “Designed BH3 Peptides with High Affinity and Specificity for Targeting Mcl-1 in Cells.” ACS Chemical Biology 9 (9): 1962-1968. doi:10.1021/cb500340w. http://dx.doi.org/10.1021/cb500340w.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-xL, 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 EC50 values of ∼3 μM, contrasted with EC50 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.Other Sources
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4168798/pdf/Terms of Use
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