Molecular wonders that are reshaping our approach to some of medicine's most challenging problems
Approved Cyclic Peptide Drugs
New Drugs Approved in 2023
Oral Bioavailability Achieved
In the endless quest for new medicines, scientists are turning to one of nature's most elegant designs: the cyclic peptide.
Imagine a key that fits a lock perfectly, able to open doors that have remained stubbornly closed to traditional medicines. This is the promise of cyclic peptides—molecular wonders that are reshaping our approach to some of medicine's most challenging problems. From powerful antibiotics that defeat superbugs to sophisticated treatments for cancer and diabetes, these natural compounds are stepping into the spotlight.
Over 40 cyclic peptide-based drugs have already been approved for clinical use, with more joining the ranks each year 2 8 . Their unique ability to target biological interactions that were once considered 'undruggable' makes them invaluable tools in our medical arsenal. This article explores how nature's intricate blueprints are being harnessed to create the next generation of therapeutics.
At their simplest, cyclic peptides are strings of amino acids—the building blocks of life—that form a closed ring instead of a straight line. This seemingly small structural detail makes a world of difference.
Compared to their linear counterparts, cyclic peptides possess a rigid three-dimensional shape that allows them to bind to their targets with exceptional precision and strength 2 . Think of a linear peptide as a floppy piece of string versus a cyclic peptide as a sturdy keyring—the latter maintains its shape and function far more effectively.
They fit their biological targets like a lock and key, reducing unwanted side effects 2 .
Their larger surface area allows them to interfere with protein-protein interactions that traditional small molecules cannot touch 5 .
Ideal for addressing targets with flat, featureless surfaces that lack deep pockets where conventional drugs bind 1 .
The medical application of cyclic peptides is already well-established, with numerous examples having transformed patient care across multiple therapeutic areas.
| Drug Name | Medical Application | Origin/Source | Key Significance |
|---|---|---|---|
| Cyclosporine A | Immunosuppression for organ transplants | Natural Product | Revolutionized transplant medicine 8 |
| Daptomycin | Antibiotic for resistant infections | Natural Product | Treats complex skin infections and bacteremia 8 |
| Zosurabalin | Novel antibiotic against resistant Acinetobacter | Synthetic | Targets Gram-negative pathogens 8 |
| Oxytocin | Stimulate uterine contractions | Natural Product | Critical for labor and delivery management 8 |
| Zilucoplan | Treat myasthenia gravis | Synthetic | 2023-approved complement C5 inhibitor 8 |
The approval of three new cyclic peptide drugs in 2023 alone—Rezafungin, Motixafortide, and Zilucoplan—demonstrates the accelerating pace of development in this field 8 . These compounds represent nature-inspired solutions to some of our most pressing medical needs.
For all their promise, cyclic peptides have faced one significant hurdle: most cannot be taken orally 1 . When swallowed, they're rapidly digested in the stomach or poorly absorbed into the bloodstream, typically forcing administration by injection 1 9 . This limitation has severely restricted their convenience and widespread use.
In 2024, researchers reported a major advance in Nature Chemical Biology: a method to develop cyclic peptides that can survive digestion and reach the bloodstream when taken orally 1 . Their innovative approach combined combinatorial chemistry with high-throughput screening to identify rare cyclic peptides that balance target affinity with oral bioavailability.
Combinatorial synthesis using 'm' random peptides × 'n' linkers × 'o' carboxylic acids created 8,448 unique cyclic peptides 1 .
One-pot synthesis and screening simultaneously testing activity and permeability identified candidates with both target binding and membrane penetration 1 .
Incubation with liver microsomes to simulate metabolic breakdown selected peptides with half-lives up to 133 minutes 1 .
Multiple cycles of synthesis and screening with modified parameters gradually improved affinity, stability, and permeability 1 .
This breakthrough demonstrates that with the right tools and approaches, the longstanding goal of oral peptide therapeutics is achievable, potentially unlocking cyclic peptides for a much broader range of medical applications.
Creating advanced cyclic peptides requires specialized methods and reagents. The field has evolved far beyond simply isolating natural compounds to include sophisticated engineering approaches that optimize their drug-like properties.
Screens vast libraries (>10^12 variants) of cyclic peptides for target binding. Identified conformation-selective PADI4 modulators .
Creates stable sulfur-based rings resistant to metabolic breakdown. Key to developing orally available peptides 1 .
Determines three-dimensional atomic structure of peptide-target complexes. Revealed allosteric activation mechanism of PADI4 by cyclic peptides .
Adds methyl groups to amide bonds to reduce hydrogen bonding capacity. Enhances membrane permeability and oral availability 1 .
These tools have enabled researchers to not only replicate nature's designs but improve upon them. For instance, strategic N-methylation—adding methyl groups to the peptide backbone—can shield polar surfaces and dramatically improve a peptide's ability to cross cell membranes, a crucial property for oral availability 1 . Similarly, advanced screening techniques like RaPID mRNA display allow scientists to sift through billions of potential candidates to find those rare peptides with desired therapeutic properties .
The field of cyclic peptide therapeutics is rapidly evolving, driven by interdisciplinary collaborations among chemists, biologists, and computational scientists 2 . Several promising directions are emerging that will likely define the next decade of research and development.
New computational tools are enabling more rational design of cyclic peptides, moving beyond trial-and-error approaches. Researchers can now predict how structural modifications will affect a peptide's stability, binding affinity, and drug-like properties before ever synthesizing it 2 .
While cyclic peptides have traditionally excelled as antibiotics and immunosuppressants, they're now being explored for metabolic diseases like diabetes and obesity 9 , with drugs like semaglutide leading the way. Their application to neurodegenerative diseases and cancer continues to expand.
Innovative delivery systems are being developed to further enhance the therapeutic potential of cyclic peptides. Peptide-drug conjugates (PDCs) that link cyclic peptides to other therapeutic agents represent a promising approach for targeted drug delivery 9 .
From the soil bacteria that gave us cyclosporine to the sophisticated synthetic compounds now entering clinical trials, cyclic peptides represent one of our most powerful strategies for addressing therapeutic challenges that have long seemed insurmountable. They occupy a unique 'chemical sweet spot'—large enough to target complex biological interactions yet small enough to possess favorable drug properties 9 .
The recent breakthrough in developing orally available cyclic peptides marks a turning point, suggesting that the full potential of these compounds is only beginning to be realized 1 . As discovery technologies mature and our understanding of structure-function relationships deepens, we can expect an accelerating pipeline of cyclic peptide therapeutics addressing an ever-widening spectrum of human diseases.
Nature has provided the blueprint. Through careful study and innovative engineering, scientists are now learning to adapt these blueprints to create the next generation of medicines—proving that sometimes, the most advanced solutions come from observing nature's timeless wisdom.