Discovery of a potent stapled helix peptide that binds to the 70N domain of replication protein A.
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Date
2014-03-27ICR Author
Author
Frank, AO
Vangamudi, B
Feldkamp, MD
Souza-Fagundes, EM
Luzwick, JW
Cortez, D
Olejniczak, ET
Waterson, AG
Rossanese, OW
Chazin, WJ
Fesik, SW
Type
Journal Article
Metadata
Show full item recordAbstract
Stapled helix peptides can serve as useful tools for inhibiting protein-protein interactions but can be difficult to optimize for affinity. Here we describe the discovery and optimization of a stapled helix peptide that binds to the N-terminal domain of the 70 kDa subunit of replication protein A (RPA70N). In addition to applying traditional optimization strategies, we employed a novel approach for efficiently designing peptides containing unnatural amino acids. We discovered hot spots in the target protein using a fragment-based screen, identified the amino acid that binds to the hot spot, and selected an unnatural amino acid to incorporate, based on the structure-activity relationships of small molecules that bind to this site. The resulting stapled helix peptide potently and selectively binds to RPA70N, does not disrupt ssDNA binding, and penetrates cells. This peptide may serve as a probe to explore the therapeutic potential of RPA70N inhibition in cancer.
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Subject
Cell Line
Alanine
Peptides
DNA, Single-Stranded
Microscopy, Fluorescence
Crystallization
Crystallography, X-Ray
Electrophoretic Mobility Shift Assay
Fluorescence Polarization
Magnetic Resonance Spectroscopy
Amino Acid Sequence
Protein Conformation
Structure-Activity Relationship
Penetrance
Models, Molecular
Molecular Sequence Data
Tumor Suppressor Protein p53
Replication Protein A
Drug Discovery
Research team
Target Evaluation and Molecular Therapeutics
Language
eng
License start date
2014-03
Citation
Journal of medicinal chemistry, 2014, 57 (6), pp. 2455 - 2461
Publisher
AMER CHEMICAL SOC