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

Zachary R. Crook, Gregory P. Sevilla, Della Friend, Mi-Youn Brusniak, Ashok D. Bandaranayake, Midori Clarke, Mesfin Gewe, Andrew J. Mhyre, David Baker, Roland K. Strong, Philip Bradley () and James M. Olson ()
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Zachary R. Crook: Fred Hutchinson Cancer Research Center
Gregory P. Sevilla: Fred Hutchinson Cancer Research Center
Della Friend: Fred Hutchinson Cancer Research Center
Mi-Youn Brusniak: Fred Hutchinson Cancer Research Center
Ashok D. Bandaranayake: Fred Hutchinson Cancer Research Center
Midori Clarke: Fred Hutchinson Cancer Research Center
Mesfin Gewe: Fred Hutchinson Cancer Research Center
Andrew J. Mhyre: Fred Hutchinson Cancer Research Center
David Baker: University of Washington, Molecular Engineering and Sciences
Roland K. Strong: Fred Hutchinson Cancer Research Center
Philip Bradley: Fred Hutchinson Cancer Research Center
James M. Olson: Fred Hutchinson Cancer Research Center

Nature Communications, 2017, vol. 8, issue 1, 1-15

Abstract: 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.

Date: 2017
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DOI: 10.1038/s41467-017-02098-8

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