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dc.contributor.authorFrank, AOen_US
dc.contributor.authorVangamudi, Ben_US
dc.contributor.authorFeldkamp, MDen_US
dc.contributor.authorSouza-Fagundes, EMen_US
dc.contributor.authorLuzwick, JWen_US
dc.contributor.authorCortez, Den_US
dc.contributor.authorOlejniczak, ETen_US
dc.contributor.authorWaterson, AGen_US
dc.contributor.authorRossanese, OWen_US
dc.contributor.authorChazin, WJen_US
dc.contributor.authorFesik, SWen_US
dc.date.accessioned2020-08-14T15:39:24Z
dc.date.issued2014-03en_US
dc.identifier.citationJournal of medicinal chemistry, 2014, 57 (6), pp. 2455 - 2461en_US
dc.identifier.issn0022-2623en_US
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/3968
dc.identifier.eissn1520-4804en_US
dc.identifier.doi10.1021/jm401730yen_US
dc.description.abstractStapled 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.en_US
dc.formatPrint-Electronicen_US
dc.format.extent2455 - 2461en_US
dc.languageengen_US
dc.language.isoengen_US
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en_US
dc.subjectCell Lineen_US
dc.subjectAlanineen_US
dc.subjectPeptidesen_US
dc.subjectDNA, Single-Strandeden_US
dc.subjectMicroscopy, Fluorescenceen_US
dc.subjectCrystallizationen_US
dc.subjectCrystallography, X-Rayen_US
dc.subjectElectrophoretic Mobility Shift Assayen_US
dc.subjectFluorescence Polarizationen_US
dc.subjectMagnetic Resonance Spectroscopyen_US
dc.subjectAmino Acid Sequenceen_US
dc.subjectProtein Conformationen_US
dc.subjectStructure-Activity Relationshipen_US
dc.subjectPenetranceen_US
dc.subjectModels, Molecularen_US
dc.subjectMolecular Sequence Dataen_US
dc.subjectTumor Suppressor Protein p53en_US
dc.subjectReplication Protein Aen_US
dc.subjectDrug Discoveryen_US
dc.titleDiscovery of a potent stapled helix peptide that binds to the 70N domain of replication protein A.en_US
dc.typeJournal Article
rioxxterms.versionofrecord10.1021/jm401730yen_US
rioxxterms.licenseref.startdate2014-03en_US
rioxxterms.typeJournal Article/Reviewen_US
dc.relation.isPartOfJournal of medicinal chemistryen_US
pubs.issue6en_US
pubs.notesNot knownen_US
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Target Evaluation and Molecular Therapeutics
pubs.publication-statusPublisheden_US
pubs.volume57en_US
pubs.embargo.termsNot knownen_US
icr.researchteamTarget Evaluation and Molecular Therapeuticsen_US
dc.contributor.icrauthorRossanese, Oliviaen_US


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Except where otherwise noted, this item's license is described as http://creativecommons.org/licenses/by/4.0/