Peptide engineering techniques like stapling, macrocyclization, and scaffold grafting are opening the door to targeting intracellular protein-protein interactions — a vast 'undruggable' space that small molecules and antibodies can't reach.
~80% of targets are 'undruggable'Most intracellular protein-protein interactions can't be reached by traditional small molecules or antibodies — engineered peptides are positioned to fill this gap
What the researchers found
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.
Why it matters
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.
How the study worked
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.
What this study cannot tell us
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.
How to read the evidence
This is a review article in a medicinal chemistry journal, synthesizing research on peptide engineering strategies. It describes technological approaches rather than clinical evidence. The individual techniques reviewed have varying levels of preclinical and early clinical validation.
When this study was published
Published in 2015, this review captured the field at an inflection point. Since then, several stapled peptide and macrocyclic peptide drug candidates have entered clinical trials, partially validating the approaches described here.
The bigger picture
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.
Questions still open
- Which peptide stabilization technique is most likely to produce the first FDA-approved intracellular PPI inhibitor?
- Can cell-penetrating peptide strategies be combined with stapling to achieve both membrane crossing and target binding?
- How do the manufacturing costs of engineered peptides compare to small molecules and antibodies?
Common questions
What makes a target 'undruggable'?
What is peptide stapling?
Read the original research
Peptide therapeutics: targeting the undruggable space.
European journal of medicinal chemistry, 94, 459-70
Citation
Tsomaia, Natia. (2015). Peptide therapeutics: targeting the undruggable space.. European journal of medicinal chemistry, 94, 459-70. https://doi.org/10.1016/j.ejmech.2015.01.014