Ultra-large chemical libraries for the discovery of high-affinity peptide binders
Models, Molecular
0301 basic medicine
Science
Q
Antibody Affinity
Antibodies, Monoclonal
Proto-Oncogene Proteins c-mdm2
Crystallography, X-Ray
Article
3. Good health
Small Molecule Libraries
03 medical and health sciences
Peptide Library
Drug Design
Drug Discovery
Amino Acid Sequence
Amino Acids
Carrier Proteins
Peptides
Chromatography, Liquid
DOI:
10.1038/s41467-020-16920-3
Publication Date:
2020-06-23T10:03:35Z
AUTHORS (9)
ABSTRACT
AbstractHigh-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.
SUPPLEMENTAL MATERIAL
Coming soon ....
REFERENCES (61)
CITATIONS (103)
EXTERNAL LINKS
PlumX Metrics
RECOMMENDATIONS
FAIR ASSESSMENT
Coming soon ....
JUPYTER LAB
Coming soon ....