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Targeting of a Helix‐Loop‐Helix Transcriptional Regulator by a Short Helical Peptide
Author(s) -
Roschger Cornelia,
Neukirchen Saskia,
Elsässer Brigitta,
Schubert Mario,
Maeding Nicole,
Verwanger Thomas,
Krammer Barbara,
Cabrele Chiara
Publication year - 2017
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201700305
Subject(s) - peptide , transcription factor , basic helix loop helix , biology , microbiology and biotechnology , cell cycle , helix (gastropod) , regulator , cell , cell growth , alpha helix , biochemistry , dna binding protein , chemistry , protein structure , gene , ecology , snail
Abstract The Id proteins (Id1–4) are cell‐cycle regulators that play a key role during development, in cancer and vascular disorders. They contain a conserved helix‐loop‐helix (HLH) domain that folds into a parallel four‐helix bundle upon self‐ or hetero‐association with basic‐HLH transcription factors. By using such protein–protein interactions, the Id proteins inhibit cell differentiation and promote cell‐cycle progression. Accordingly, their supporting role in cancer has been convincingly demonstrated, which makes these proteins interesting therapeutic targets. Herein we present a short peptide containing an (i,i+4)‐lactam bridge and a hydrophobic (Φ) three‐residue motif Φ(i)−Φ(i+3)−Φ(i+6), which adopts a helical conformation in water, shows Id protein binding in the low‐micromolar range, penetrates into breast (MCF‐7 and T47D) and bladder (T24) cancer cells, accumulates in the nucleus, and decreases cell viability to ∼50 %. Thus, this cyclopeptide is a promising scaffold for the development of Id protein binders that impair cancer cell viability.