Issue 32, 2021

Automated affinity selection for rapid discovery of peptide binders


In-solution affinity selection (AS) of large synthetic peptide libraries affords identification of binders to protein targets through access to an expanded chemical space. Standard affinity selection methods, however, can be time-consuming, low-throughput, or provide hits that display low selectivity to the target. Here we report an automated bio-layer interferometry (BLI)-assisted affinity selection platform. When coupled with tandem mass spectrometry (MS), this method enables both rapid de novo discovery and affinity maturation of known peptide binders with high selectivity. The BLI-assisted AS-MS technology also features real-time monitoring of the peptide binding during the library selection process, a feature unattainable by current selection approaches. We show the utility of the BLI AS-MS platform toward rapid identification of novel nanomolar (dissociation constant, KD < 50 nM) non-canonical binders to the leukemia-associated oncogenic protein menin. To our knowledge, this is the first application of BLI to the affinity selection of synthetic peptide libraries. We believe our approach can significantly accelerate the use of synthetic peptidomimetic libraries in drug discovery.

Graphical abstract: Automated affinity selection for rapid discovery of peptide binders

Supplementary files

Article information

Article type
Edge Article
11 May 2021
13 Jul 2021
First published
14 Jul 2021
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY license

Chem. Sci., 2021,12, 10817-10824

Automated affinity selection for rapid discovery of peptide binders

G. Zhang, C. Li, A. J. Quartararo, A. Loas and B. L. Pentelute, Chem. Sci., 2021, 12, 10817 DOI: 10.1039/D1SC02587B

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