Journal
NATURE CHEMICAL BIOLOGY
Volume 15, Issue 4, Pages 410-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41589-019-0245-2
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Funding
- Bettencourt Schueller Foundation [LT000745/2014-C]
- Servier
- Defense Advanced Research Projects Agency [023504-001]
- NIH National Institute of General Medical Sciences [5-R01-GM110535]
- Bristol-Myers Squibb
- Novartis Early Career Award
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The use of competitive inhibitors to disrupt protein-protein interactions (PPIs) holds great promise for the treatment of disease. However, the discovery of high-affinity inhibitors can be a challenge. Here we report a platform for improving the affinity of peptide-based PPI inhibitors using non-canonical amino acids. The platform utilizes size exclusion-based enrichment from pools of synthetic peptides (1.5-4 kDa) and liquid chromatography-tandem mass spectrometry-based peptide sequencing to identify high-affinity binders to protein targets, without the need for 'reporter' or 'encoding' tags. Using this approach-which is inherently selective for high-affinity binders-we realized gains in affinity of up to similar to 100- or similar to 30-fold for binders to the oncogenic ubiquitin ligase MDM2 or HIV capsid protein C-terminal domain, which inhibit MDM2-p53 interaction or HIV capsid protein C-terminal domain dimerization, respectively. Subsequent macrocyclization of select MDM2 inhibitors rendered them cell permeable and cytotoxic toward cancer cells, demonstrating the utility of the identified compounds as functional PPI inhibitors.
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