title: Designed BH3 peptides with high affinity and specificity for targeting Mcl-1 in cells.
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.
authors: Department of Biology, Massachusetts Institute of Technology , Cambridge, Massachusetts 02139, United States.
authors: Glenna Wink
authors: GW
authors: Foight
authors: Jeremy A
authors: JA
authors: Ryan
authors: Stefano V
authors: SV
authors: Gullá
authors: Anthony
authors: A
authors: Letai
authors: Amy E
authors: AE
authors: Keating
mesh_terms: D051017:Apoptosis Regulatory Proteins / Q000737:chemistry / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D002460:Cell Line / Q000187:drug effects; D061505:Cell Surface Display Techniques / Q000379:methods; D005454:Fluorescence Polarization; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism; D015778:Minor Histocompatibility Antigens; D058990:Molecular Targeted Therapy / Q000379:methods*; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D013912:Threonine / Q000737:chemistry / Q000378:metabolism; D051020:bcl-X Protein / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; C096816:BCL2-related protein A1; C494811:BCL2L1 protein, human; C000606775:BCL2L11 protein, human; C491073:BCL2L2 protein, human; C474007:Bax protein (53-86); D000072224:Bcl-2-Like Protein 11; C579095:MCL1 protein, human; D008565:Membrane Proteins; D015778:Minor Histocompatibility Antigens; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D010446:Peptide Fragments; D010455:Peptides; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; D013912:Threonine