Pentelute Lab MIT | Ultra-large chemical libraries for the discovery of high-affinity peptide binders
The Pentelute Lab aims to invent new chemistry for the efficient and selective modification of proteins, to ‘hijack’ these biological machines for efficient drug delivery into cells and to create new machines to rapidly and efficiently manufacture peptides and proteins.
Pentelute Lab, Chemistry, MIT, Chemistry Department, Boston, Cambridge, Biology, Peptides, Peptide, Proteins, Science, Rapid, Brad Pentelute, Brad,
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Ultra-large chemical libraries for the discovery of high-affinity peptide binders

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

Nature Communications volume 11, Article number: 3183 (2020)
Anthony J. Quartararo, Zachary P. Gates, Bente A. Somsen, Nina Hartrampf, Xiyun Ye, Arisa Shimada, Yasuhiro Kajihara, Christian Ottmann & Bradley L. Pentelute

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.

Category
2020, Publications