Potent and specific peptide inhibitors of human pro-survival protein Bcl-xL.

TitlePotent and specific peptide inhibitors of human pro-survival protein Bcl-xL.
Publication TypeJournal Article
Year of Publication2015
AuthorsDutta S, Ryan J, T Chen S, Kougentakis C, Letai A, Keating AE
JournalJ Mol Biol
Volume427
Issue6 Pt B
Pagination1241-53
Date Published2015 Mar 27
ISSN1089-8638
KeywordsAmino Acid Sequence, Apoptosis, Apoptosis Regulatory Proteins, bcl-X Protein, Breast Neoplasms, Female, Humans, Models, Molecular, Molecular Sequence Data, Peptide Fragments, Peptide Library, Protein Conformation, Proto-Oncogene Proteins c-bcl-2, Saccharomyces cerevisiae, Tumor Cells, Cultured
Abstract

The Bcl-2 family of proteins plays a critical role regulating apoptosis, and pro-survival Bcl-2 family members are important therapeutic targets due to their overexpression in different cancers. Pro-apoptotic Bcl-2 homology 3 (BH3)-only proteins antagonize pro-survival Bcl-2 protein functions by binding directly to them, and a sub-class of BH3-only proteins termed sensitizers can initiate apoptosis via this mechanism in response to diverse signals. The five pro-survival proteins Bcl-xL, Mcl-1, Bcl-2, Bcl-w and Bfl-1 differ in their binding preferences, with Bcl-xL, Bcl-2 and Bcl-w sharing similar interaction profiles for many natural sensitizers and small molecules. Peptides that bind selectively to just one or a subset of family members have shown utility in assays that diagnose apoptotic blockades in cancer cells and as reagents for dissecting apoptotic mechanism. Combining computational design, combinatorial library screening and rational mutagenesis, we designed a series of BH3 sensitizer peptides that bind Bcl-xL with sub-nanomolar affinity and selectivity up to 1000-fold over each of the four competing pro-survival proteins. We demonstrate the efficacy of our designed BH3 peptides in assays that differentiate between cancer cells that are dependent on different pro-survival proteins.

DOI10.1016/j.jmb.2014.09.030
Alternate JournalJ. Mol. Biol.
PubMed ID25451027
PubMed Central IDPMC4357494
Grant ListCA129974 / CA / NCI NIH HHS / United States
GM110048 / GM / NIGMS NIH HHS / United States
P50 GM068762 / GM / NIGMS NIH HHS / United States
P50-GM068762 / GM / NIGMS NIH HHS / United States
R01 CA129974 / CA / NCI NIH HHS / United States
R01 GM110048 / GM / NIGMS NIH HHS / United States
R21 CA188858 / CA / NCI NIH HHS / United States
T32 GM007287 / GM / NIGMS NIH HHS / United States