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Publication Abstract from PubMed

High-diversity genetically-encoded combinatorial libraries (10(8)-10(13) 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 ~ 10(6) 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 10(8) 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 10(6)-10(8). These results are then applied to the discovery of p53-like binders to MDM2, and to a family of 3-19 nM-affinity, alpha/beta-peptide-based binders to 14-3-3. An X-ray structure of one of these binders in complex with 14-3-3sigma is determined, illustrating the role of beta-amino acids in facilitating a key binding contact.

Ultra-large chemical libraries for the discovery of high-affinity peptide binders.,Quartararo AJ, Gates ZP, Somsen BA, Hartrampf N, Ye X, Shimada A, Kajihara Y, Ottmann C, Pentelute BL Nat Commun. 2020 Jun 23;11(1):3183. doi: 10.1038/s41467-020-16920-3. PMID:32576815^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.