Peptidomimetics — molecules that mimic peptide structure but resist degradation — bridge the gap between small-molecule drugs and biologics, enabling therapeutic targeting of previously 'undruggable' protein-protein interactions.
Targeting the 'undruggable'Peptidomimetics combine peptide-like binding surfaces with drug-like stability, successfully modulating protein-protein interactions that conventional small molecules and biologics cannot reach
What the researchers found
Peptidomimetics — particularly stapled peptides and macrocyclic peptides — have been successfully applied to target numerous 'undruggable' protein-protein interactions, combining the targeting capability of peptides with improved pharmacokinetic properties through conformational constraint.
Why it matters
Most disease-relevant protein-protein interactions cannot be targeted by conventional small-molecule drugs, creating a vast untapped therapeutic space that peptidomimetics can uniquely address.
How the study worked
Narrative review of chemical approaches for creating conformationally constrained peptidomimetics, focusing on stapled peptides and macrocyclization strategies, with examples of successful biological applications.
What this study cannot tell us
As a 2018 review, it may not cover the most recent advances in peptidomimetic chemistry and clinical development. The review focuses on chemical approaches without detailed discussion of manufacturing, cost, or clinical translation challenges.
How to read the evidence
This is a narrative review covering the chemical and biological aspects of peptidomimetic development. It provides a comprehensive overview of the field but does not present new experimental data.
When this study was published
Published in 2018, this review captured the peptidomimetics field during its transition from academic research to clinical development. The field has continued to advance rapidly since publication.
The bigger picture
Peptidomimetics represent the third wave of drug development — after small molecules and biologics. By occupying the middle ground in size and properties, they can reach therapeutic targets inaccessible to either conventional modality. The concept of 'drugging the undruggable' through constrained peptide-like molecules has moved from academic curiosity to clinical reality, with stapled peptides entering clinical trials for cancer and other diseases. This review captures the field at a pivotal transition from proof-of-concept to therapeutic pipeline.
Questions still open
- Which peptidomimetic platforms are closest to achieving FDA approval for targeting PPIs?
- Can AI-driven design accelerate the optimization of peptidomimetic drug candidates?
- How will peptidomimetics compete with or complement antibody-based approaches for PPI modulation?
Common questions
What is a peptidomimetic?
Why are protein-protein interactions so hard to target with drugs?
Read the original research
Peptidomimetics Targeting Protein-Protein Interactions for Therapeutic Development.
Protein and peptide letters, 25(12), 1076-1089
Citation
Zhang, Gan; Andersen, Jessica; Gerona-Navarro, Guillermo. (2018). Peptidomimetics Targeting Protein-Protein Interactions for Therapeutic Development.. Protein and peptide letters, 25(12), 1076-1089. https://doi.org/10.2174/0929866525666181101100842