Inhibition and stabilization of protein-protein interactions

Protein–protein interactions (PPIs) form the molecular basis for almost every phenomenon of life including signal perception and transduction, movement, gene expression, and cell cycle control, and hence play important roles in human health and disease. The estimated number of PPIs in the human body, in the range of 300,000 1 to 650,000, 2 by far exceeds the number of protein targets that can be addressed by classical small-molecule approaches, like active-site inhibition or modulation of cell surface receptors or ion channels. Consequently, pharmacological interventions of PPIs has increasingly attracted attention from chemical biology and bioorganic- and medicinal chemistry, and a number of excellent reviews on the topic have been published in recent years. 3–9 This Bioorganic and Medicinal Chemistry special issue on inhibition and stabilization of protein–protein interactions contains a collection of original papers and reviews covering important technological aspects of prominent PPI target classes. In a contribution by Doemling and co-workers, inhibition of the cancer-relevant Mdm2/p53 interaction by benzimidazolones is reported. Burke and colleagues describe the design, synthesis and activity of phosphomimetic-containing peptides targeting the polo-box domain (PDB) of Plk1. Ohkanda and colleagues demonstrate how peptidomimetic modification enhances membrane permeability and cellular activity of a farnesyl transferas