How Engineered Peptides Could Drug the 'Undruggable' — Targeting Protein Interactions Inside Cells

The review highlights recent technological and chemical advancements in peptide design that enable targeting of intracellular protein-protein interactions, a class of targets traditionally considered undruggable by small molecules or biologics.

This is a review article summarizing current research and technological progress in peptide therapeutics, focusing on chemical strategies such as stapling and macrocyclization to stabilize peptides for intracellular targeting.

This work is important because it outlines how peptides can overcome limitations of existing drugs, potentially leading to new treatments for diseases involving intracellular protein interactions.

The 'undruggable' proteome represents roughly 80% of disease-relevant targets. Protein-protein interactions control cancer pathways (p53-MDM2), apoptosis (Bcl-2 family), and transcription factors that drive disease. Since 2015, several of the approaches described in this review have advanced to clinical trials — stapled peptides targeting MDM2 and Bcl-2 have shown promise. The concept of 'beyond rule-of-five' drug design, where molecules exceed traditional small-molecule size limits, has become a major pharmaceutical research theme.

As a review, it does not present new experimental data and the evidence strength and clinical applicability of discussed approaches remain to be fully established.