Application of Post Solid-Phase Oxime Ligation to Fine-Tune Peptide–Protein Interactions

Protein–protein interactions (PPIs) represent an extremely attractive class of potential new targets for therapeutic intervention; however, the shallow extended character of many PPIs can render developing inhibitors against them as exceptionally difficult. Yet this problem can be made tractable by taking advantage of the fact that large interacting surfaces are often characterized by confined “hot spot” regions, where interactions contribute disproportionately to overall binding energies. Peptides afford valuable starting points for developing PPI inhibitors because of their high degrees of functional diversity and conformational adaptability. Unfortunately, contacts afforded by the 20 natural amino acids may be suboptimal and inefficient for accessing both canonical binding interactions and transient “cryptic” binding pockets. Oxime ligation represents a class of biocompatible “click” chemistry that allows the structural diversity of libraries of aldehydes to be rapidly evaluated within the context of a parent oxime-containing peptide platform. Importantly, oxime ligation represents a form of post solid-phase diversification, which provides a facile and empirical means of identifying unanticipated protein–peptide interactions that may substantially increase binding affinities and selectivity. The current review will focus on the authors’ use of peptide ligation to optimize PPI antagonists directed against several targets, including tumor susceptibility gene 101 (Tsg101), protein tyrosine phosphatases (PTPases) and the polo-like kinase 1 (Plk1). This should provide insights that can be broadly directed against an almost unlimited range of physiologically important PPIs.