Cyclic Peptides Are Unlocking Previously 'Undruggable' Disease Targets | Research

The takeaway

Stabilized cyclic peptides — through helix stapling, β-hairpin mimicry, and macrocyclization — are emerging as the most promising approach to drug protein-protein interactions that conventional medicines cannot reach.

Targeting 'undruggable' interactions
Stabilized cyclic peptides overcome the poor proteolysis resistance and cell permeability of linear peptides to modulate protein-protein interactions that conventional drugs cannot reach

What the researchers found

Cyclic peptides have improved stability and bioavailability, making them viable PPI modulators.

Why it matters

Targeting protein-protein interactions is crucial for developing new therapies for diseases, and cyclic peptides offer a promising approach to overcome challenges in this area.

How the study worked

The study is a comprehensive review of recent advancements in cyclic peptide design and their applications in modulating PPIs.

What this study cannot tell us

As a review, the study does not present original experimental data and focuses on summarizing existing literature.

How to read the evidence

This is a comprehensive review of the cyclic peptide field covering chemistry, biology, and therapeutic development. It synthesizes evidence from numerous studies but does not present new experimental data.

When this study was published

Published in 2023, this review captures the state of cyclic peptide technology during a period of rapid advancement, with multiple candidates in clinical trials and new chemical methodologies emerging regularly.

The bigger picture

An estimated 80% of disease-relevant proteins cannot be targeted by conventional drugs. Cyclic peptides are bridging the gap between small molecules (too small for PPIs) and antibodies (too large to enter cells). The rapid development over the past two decades — from basic chemistry to drugs in clinical trials — signals a maturation of cyclic peptide technology. As manufacturing and delivery challenges are resolved, cyclic peptides could unlock an entirely new generation of therapeutics for cancer, autoimmune diseases, and infectious diseases that have resisted conventional drug approaches.

Questions still open

Which 'undruggable' PPIs are closest to being targeted by cyclic peptides in clinical development?
Can AI-driven design accelerate the discovery of cell-permeable, orally bioavailable cyclic peptides?
Will cyclic peptide drugs be cost-competitive with antibody therapeutics and small molecules?

Common questions

What are cyclic peptides and why are they special?

Cyclic peptides are short protein chains whose ends are linked to form a ring. This circular structure makes them much more stable than linear peptides — they resist digestive enzymes and can enter cells more easily. Their medium size (between small drugs and large antibodies) lets them target protein surfaces that are too large for conventional drugs but too small for antibodies, opening up entirely new disease targets.

What diseases could cyclic peptide drugs treat?

Cyclic peptides are being developed for cancer (disrupting tumor growth signaling), autoimmune diseases (blocking immune protein interactions), infectious diseases, and many conditions driven by protein-protein interactions that current drugs can't address. Several cyclic peptide drugs are already in clinical trials, with the field accelerating rapidly.

Read the original research

Stabilized cyclic peptides as modulators of protein-protein interactions: promising strategies and biological evaluation.

RSC medicinal chemistry, 14(12), 2496-2508

View on PubMed ↗Publisher’s paper ↗

Citation

Cheng, Jiongjia; Zhou, Junlong; Kong, Lingyan; Wang, Haiying; Zhang, Yuchi; Wang, Xiaofeng; Liu, Guangxiang; Chu, Qian. (2023). Stabilized cyclic peptides as modulators of protein-protein interactions: promising strategies and biological evaluation.. RSC medicinal chemistry, 14(12), 2496-2508. https://doi.org/10.1039/d3md00487b