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

• DOI: 10.1038/s41467-020-16920-3
• Publication Date: 2020-06-23T10:03:35Z
• Authors: Anthony J. Quarta...; Zachary P. Gates; Bente A. Somsen; Nina Hartrampf; Xiyun Ye; Arisa Shimada; Yasuhiro Kajihara; Christian Ottmann; Bradley L. Pentelute
• Keywords: Chemical space; Tandem

Abstract 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 can access broader chemical space, but typically examine only ~ 10 6 compounds screening. Here we show that in-solution selection be interfaced with nano-liquid chromatography-tandem mass spectrometry peptide sequencing to identify binders from fully randomized synthetic members—a 100-fold gain in diversity over standard practice. To validate this approach, monoclonal antibody proportion library diversity, as is increased –10 . These results then applied the discovery p53-like MDM2, and family 3–19 nM-affinity, α/β-peptide-based 14-3-3. An X-ray structure one these complex 14-3-3σ determined, illustrating role β-amino acids facilitating key contact.