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.
CITATION STYLE
Crook, Z. R., Sevilla, G. P., Friend, D., Brusniak, M. Y., Bandaranayake, A. D., Clarke, M., … Olson, J. M. (2017). Mammalian display screening of diverse cystine-dense peptides for difficult to drug targets. Nature Communications, 8(1). https://doi.org/10.1038/s41467-017-02098-8
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