title: Challenges in Targeting a Basic Helix-Loop-Helix Transcription Factor with Hydrocarbon-Stapled Peptides.
abstract: Basic helix-loop-helix (bHLH) transcription factors play critical roles in organism development and disease by regulating cell proliferation and differentiation. Transcriptional activity, whether by bHLH homo- or heterodimerization, is dependent on protein-protein and protein-DNA interactions mediated by α-helices. Thus, α-helical decoys have been proposed as potential targeted therapies for pathologic bHLH transcription. Here, we developed a library of stabilized α-helices of OLIG2 (SAH-OLIG2) to test the capacity of hydrocarbon-stapled peptides to disrupt OLIG2 homodimerization, which drives the development and chemoresistance of glioblastoma multiforme, one of the deadliest forms of human brain cancer. Although stapling successfully reinforced the α-helical structure of bHLH constructs of varying length, sequence-specific dissociation of OLIG2 dimers from DNA was not achieved. Re-evaluation of the binding determinants for OLIG2 self-association and stability revealed an unanticipated role of the C-terminal domain. These data highlight potential pitfalls in peptide-based targeting of bHLH transcription factors given the liabilities of their positively charged amino acid sequences and multifactorial binding determinants.
authors.affiliation: Department of Pediatric Oncology and the Linde Program in Cancer Chemical Biology, Dana-Farber Cancer Institute , Boston, Massachusetts 02215, United States.
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Edwards
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute , Boston, Massachusetts 02215, United States.
authors.forename: Dimphna H
authors.initials: DH
authors.lastname: Meijer
authors.affiliation: Department of Pediatric Oncology and the Linde Program in Cancer Chemical Biology, Dana-Farber Cancer Institute , Boston, Massachusetts 02215, United States.
authors.forename: Rachel M
authors.initials: RM
authors.lastname: Guerra
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute , Boston, Massachusetts 02215, United States.
authors.forename: Remco J
authors.initials: RJ
authors.lastname: Molenaar
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute , Boston, Massachusetts 02215, United States.
authors.forename: John A
authors.initials: JA
authors.lastname: Alberta
authors.affiliation: Department of Pediatric Oncology and the Linde Program in Cancer Chemical Biology, Dana-Farber Cancer Institute , Boston, Massachusetts 02215, United States.
authors.forename: Federico
authors.initials: F
authors.lastname: Bernal
authors.affiliation: Department of Pediatric Oncology and the Linde Program in Cancer Chemical Biology, Dana-Farber Cancer Institute , Boston, Massachusetts 02215, United States.
authors.forename: Gregory H
authors.initials: GH
authors.lastname: Bird
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute , Boston, Massachusetts 02215, United States.
authors.forename: Charles D
authors.initials: CD
authors.lastname: Stiles
authors.affiliation: Department of Pediatric Oncology and the Linde Program in Cancer Chemical Biology, Dana-Farber Cancer Institute , Boston, Massachusetts 02215, United States.
authors.forename: Loren D
authors.initials: LD
authors.lastname: Walensky
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D019556:COS Cells; D019281:Dimerization; D006801:Humans; D006838:Hydrocarbons / Q000737:chemistry*; D018716:Molecular Mimicry; D010455:Peptides / Q000737:chemistry*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D006838:Hydrocarbons; D010455:Peptides