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Crook, Zachary R; Sevilla, Gregory P; Friend, Della; Brusniak, Mi-Youn; Bandaranayake, Ashok D; Clarke, Midori; Gewe, Mesfin; Mhyre, Andrew J; Baker, David; Strong, Roland K; Bradley, Philip; Olson, James M
Nature communications, 12/2017, Letnik: 8, Številka: 1Journal Article
Protein:protein interactions are among the most difficult to treat molecular mechanisms of disease pathology. Cystine-dense peptides have the potential to disrupt such interactions, and are used in drug-like roles by every clade of life, but their study has been hampered by a reputation for being difficult to produce, owing to their complex disulfide connectivity. Here we describe a platform for identifying target-binding cystine-dense peptides using mammalian surface display, capable of interrogating high quality and diverse scaffold libraries with verifiable folding and stability. We demonstrate the platform's capabilities by identifying a cystine-dense peptide capable of inhibiting the YAP:TEAD interaction at the heart of the oncogenic Hippo pathway, and possessing the potency and stability necessary for consideration as a drug development candidate. This platform provides the opportunity to screen cystine-dense peptides with drug-like qualities against targets that are implicated for the treatment of diseases, but are poorly suited for conventional approaches.
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in: SICRIS
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