Mammalian display screening of diverse cystine-dense peptides for difficult to drug targets

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Abstract

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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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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