Pentelute Lab MIT | In-solution enrichment identifies peptide inhibitors of protein–protein interactions
The Pentelute Lab aims to invent new chemistry for the efficient and selective modification of proteins, to ‘hijack’ these biological machines for efficient drug delivery into cells and to create new machines to rapidly and efficiently manufacture peptides and proteins.
Pentelute Lab, Chemistry, MIT, Chemistry Department, Boston, Cambridge, Biology, Peptides, Peptide, Proteins, Science, Rapid, Brad Pentelute, Brad,
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In-solution enrichment identifies peptide inhibitors of protein–protein interactions

In-solution enrichment identifies peptide inhibitors of protein–protein interactions

Nature Chemical Biologyvolume 15, pages410–418 (2019)
Fayçal Touti, Zachary P. Gates, Anupam Bandyopadhyay, Guillaume Lautrette & Bradley L. Pentelute

Abstract

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 ~100- or ~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.

Category
2019, Publications