Targeting protein-protein interactions can provide plentiful opportunities for the discovery of novel drug candidates and powerful chemical biology tools. However, the majority of these interactions are ‘undruggable”, and we still know very little about the structural mechanisms and functions for the vast majority of them. We have developed a rational approach that allows for the straightforward development of cell-permeable metabolically stable inhibitors of protein-protein interactions. The approach is based on structural stabilization of peptides by membrane anchoring.  Proximity to the membrane facilitates interactions of hydrophobic side chains of amphiphilic peptides with the bilayer and stabilizes natural folds of not only helical but also stretched and hairpin-type peptides. Membrane tethering is achieved through facile derivatization of peptides with fatty acids of appropriate length that depends on peptide’s hydrophobicity. Lipidation facilitates cell entry and allows intracellular delivery of peptides up to 14-16 residues long. Negative charges can interfere with the entry, while positive charges generally have little effect. Wide applicability of this method was confirmed by generation of selective and highly potent dominant negative inhibitors of RAS oncogenes, b-catenin, STAT1, STAT3 and STAT5 N-domains, Il10R1, IFNGR1 and other non-druggable targets. Rational design of inhibitors can be accomplished even in the absence of the target tertiary structure by using conservation of certain sequence parts during the evolution.  High throughput generation of selective chemical biology tools allows for effective interrogation of protein-protein interactions leading to discovery of mechanistic details of molecular signaling that could not be obtained with the help of genetic approaches.

Generation of  cell-permeable protein mimetics through structural stabilization of protein fragments by membrane anchoring

256th National Meeting (2018)

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