Author
Listed:
- 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)
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.
Suggested Citation
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 & Jam, 2017.
"Mammalian display screening of diverse cystine-dense peptides for difficult to drug targets,"
Nature Communications, Nature, vol. 8(1), pages 1-15, December.
Handle:
RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-02098-8
DOI: 10.1038/s41467-017-02098-8
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