Ultra-large chemical libraries for the discovery of high-affinity peptide binders
Name
s41467-020-16920-3.pdf
Description
Published version
Size
1.11 MB
Format
Adobe PDF
Checksum (MD5)
95741d6c6542c114f03106b312852876
Author(s)
Quartararo, Anthony James
Gates, Zachary P
Somsen, Bente A.
Hartrampf, Nina
Ye, Xiyun
Shimada, Arisa
Kajihara, Yasuhiro
Ottmann, Christian
Pentelute, Bradley L.
Date Issued
June 2020
Journal
Nature Communications
Publisher
Springer Science and Business Media LLC
Citation
Quartararo, Anthony J. et al. "Ultra-large chemical libraries for the discovery of high-affinity peptide binders." Nature Communications 11, 1 (June 2020): 3183 © 2020 The Author(s)
Version
Final published version
Abstract
High-diversity genetically-encoded combinatorial libraries (108−1013 members) are a rich source of peptide-based binding molecules, identified by affinity selection. Synthetic libraries can access broader chemical space, but typically examine only ~ 106 compounds by screening. Here we show that in-solution affinity selection can be interfaced with nano-liquid chromatography-tandem mass spectrometry peptide sequencing to identify binders from fully randomized synthetic libraries of 108 members—a 100-fold gain in diversity over standard practice. To validate this approach, we show that binders to a monoclonal antibody are identified in proportion to library diversity, as diversity is increased from 106–108. These results are then applied to the discovery of p53-like binders to MDM2, and to a family of 3–19 nM-affinity, α/β-peptide-based binders to 14-3-3. An X-ray structure of one of these binders in complex with 14-3-3σ is determined, illustrating the role of β-amino acids in facilitating a key binding contact.
MIT Department
Massachusetts Institute of Technology. Department of Chemistry
Massachusetts Institute of Technology. Center for Environmental Health Sciences
Koch Institute for Integrative Cancer Research at MIT
Terms of Use
Creative Commons Attribution 4.0 International license
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DOI of Published Version
https://doi.org/10.1038/s41467-020-16920-3
