Ultra-large chemical libraries for the discovery of high-affinity peptide binders

Anthony J. Quartararo, Zachary P. Gates, Bente A. Somsen, Nina Hartrampf, Xiyun Ye, Arisa Shimada, Yasuhiro Kajihara, Christian Ottmann and Bradley L. Pentelute ()
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Anthony J. Quartararo: Massachusetts Institute of Technology
Zachary P. Gates: Massachusetts Institute of Technology
Bente A. Somsen: Eindhoven University of Technology
Nina Hartrampf: Massachusetts Institute of Technology
Xiyun Ye: Massachusetts Institute of Technology
Arisa Shimada: Osaka University
Yasuhiro Kajihara: Osaka University
Christian Ottmann: Eindhoven University of Technology
Bradley L. Pentelute: Massachusetts Institute of Technology

Nature Communications, 2020, vol. 11, issue 1, 1-11

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-16920-3

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