Researchers have developed a new enzymatic process that transforms therapeutic peptides into durable, ring-shaped structures, a breakthrough that could lead to more potent and longer-lasting medications for diabetes and obesity. The method provides a simple, “plug-and-play” solution to the persistent problem of instability that has long challenged developers of popular GLP-1 drugs like semaglutide, the active ingredient in Ozempic and Wegovy.
The discovery, detailed by a team at the University of Utah, centers on a specialized enzyme that “ties off” the ends of GLP-1-like peptides, shielding them from the body’s natural recycling machinery. This process, known as macrocyclization, has traditionally been difficult and costly to achieve using conventional chemistry, especially late in the drug development cycle. By creating a biocatalytic shortcut, the new technique offers a highly efficient way to enhance the stability of these powerful therapeutic molecules, potentially reducing dosing frequency and improving patient outcomes.
The Challenge of Peptide Instability
GLP-1-based drugs have revolutionized the treatment of type 2 diabetes and obesity by signaling the body to produce insulin more naturally. However, the peptides at their core are inherently fragile. The human body is equipped with enzymes called proteases that rapidly digest peptides and proteins into their constituent amino acids, recycling them for other uses. This natural process means that therapeutic peptides like GLP-1 degrade quickly in the bloodstream, sometimes in a matter of minutes. This short half-life is a significant hurdle, as a drug’s effectiveness plummets if it cannot last long enough to exert its biological effect.
To overcome this, drug developers have employed various strategies, from modifying peptide backbones with synthetic chemistry to fusing them with larger, more stable molecules. While effective, these methods can be complex, expensive, and may require significant re-engineering of the drug from its earliest stages. Finding a way to stabilize these molecules efficiently is crucial for creating the next generation of more convenient and effective treatments.
A Novel Enzymatic Approach
The Utah researchers discovered that an enzyme they dubbed PapB can perform this stabilization task with remarkable precision and flexibility. PapB belongs to a class of enzymes known as “radical SAM” enzymes and works by forging a resilient sulfur-carbon bond, or thioether, that connects the two ends of a peptide chain. This action effectively transforms the linear peptide into a closed, circular structure—a process called macrocyclization. This ring-like shape is not just more robust; it strategically hides the ends of the peptide from the proteases that would normally break it down.
In laboratory tests, the team demonstrated that the PapB enzyme could be applied to three different GLP-1-like peptides, successfully converting each one into its ringed, or macrocyclic, version. The enzyme proved capable of handling peptides that included nonstandard building blocks, which are common components of modern, highly optimized incretin drugs used to treat metabolic disorders. This adaptability makes it a powerful tool for modern pharmaceutical research.
Key Advantages of the Biocatalytic Method
The true innovation of the PapB system lies in its simplicity and versatility, which set it apart from other enzymatic modification techniques.
Leader-Independent Modification
Many peptide-modifying enzymes require the presence of a special molecular tag, called a “leader sequence,” on the target peptide to function correctly. This requirement limits their use, as the leader tag must be attached before the reaction and then cleaved off afterward. The researchers found that PapB is a rare exception; it works without any leader sequence. This leader-independent capability means it can be applied directly to a wide array of existing peptides, making it a far more practical and straightforward tool for drug developers.
Late-Stage Application
Because PapB is so flexible and requires no preliminary peptide modification, it can serve as a “plug-and-play” biocatalyst. This allows researchers to apply it late in the drug development pipeline. They can take an already promising peptide candidate—one that has been optimized for potency and efficacy—and then use the enzyme to enhance its stability as a final step. This avoids the need for costly and time-consuming redesigns that conventional chemical macrocyclization might require.
Experimental Findings and Publication
The proof-of-concept study confirmed the enzyme’s effectiveness and surprising adaptability. “We were surprised by how flexible the enzyme turned out to be,” said Jake Pedigo, the study’s lead author and a graduate student at the University of Utah. The team’s research demonstrated that PapB provides a reliable method for fortifying GLP-1 peptides, which could have a significant impact on existing therapeutics.
By using this enzymatic method to tie off the ends of the peptides, the molecules are essentially hidden from the body’s most common proteases. This protection is what would enable a longer half-life, extending the drug’s therapeutic window from minutes to hours or even days. The findings were published in the American Chemical Society journal ACS Bio & Med Chem Au under the title, “Leader-Independent C-Terminal Modification by a Radical S-Adenosyl-L-methionine Maturase Enables Macrocyclic GLP-1-Like Peptides.”
Implications for Future Drug Design
The development of this biocatalytic shortcut has significant implications for the future of peptide-based medicines. The ability to easily create more stable GLP-1 drugs could lead to treatments that require less frequent administration, improving convenience and adherence for patients managing chronic conditions like diabetes and obesity. Furthermore, the robustness of the method opens the door to creating entirely new therapeutic designs that are sturdier and more targeted.
The research shows it is possible to enhance the properties of the excellent GLP-1 backbones that pharmaceutical companies have already developed. Instead of starting from scratch, drug makers could potentially use this enzymatic process to improve market-approved therapeutics, extending their effectiveness and value. This approach could ultimately accelerate the delivery of better, longer-lasting treatments for metabolic diseases to the clinic.
