Ultra-large chemical libraries for the discovery of high-affinity peptide binders
Author(s)
Quartararo, Anthony James; Gates, Zachary P; Somsen, Bente A.; Hartrampf, Nina; Ye, Xiyun; Shimada, Arisa; Kajihara, Yasuhiro; Ottmann, Christian; Pentelute, Bradley L.; ... Show more Show less
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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.
Date issued
2020-06Department
Massachusetts Institute of Technology. Department of Chemistry; Massachusetts Institute of Technology. Center for Environmental Health Sciences; Koch Institute for Integrative Cancer Research at MITJournal
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
ISSN
2041-1723