Scientists have pioneered a novel method for synthesizing peptides, potentially enhancing the efficiency and cost-effectiveness of drug manufacturing.
Currently, over 70 peptide-based drugs are approved for clinical use, addressing conditions like diabetes, cancer, and HIV, with numerous others under development. As the demand for peptide treatments rises, advancements in peptide manufacturing technologies are crucial to meeting future needs.
Researchers at Imperial College London have developed PEPSTAR, an innovative technique that accelerates peptide synthesis without compromising quality. This method, scalable for commercial use, could also be applied to the production of other sequence-defined polymers in various fields. The findings are published in Angewandte Chemie.
Addressing Solid and Liquid Phase Challenges
Peptide synthesis requires the precise assembly of amino acids. The ability to remove excess amino acids before adding new ones is a critical step in this process.
Professor Andrew Livingston from the Department of Chemical Engineering explains, “PEPSTAR is a more flexible platform compared to the classic solid phase method, and it provides more options for further optimizations of the peptide manufacturing process.”
The traditional solid phase method couples amino acids to insoluble supports, which are then washed to remove excess amino acids. This method is easily automated for rapid synthesis in a single reactor. However, it faces scaling challenges due to “diffusional limitations,” where amino acids must diffuse into the solid resin beads. These limitations can lead to incomplete reactions and low peptide purity, requiring excess reagents and increasing costs.
The liquid phase method, where supports are soluble, avoids these diffusional limitations, resulting in higher purity peptides and less need for excess reagents. However, slow and complex extraction or precipitation methods have hindered its scalability and automation.
PEPSTAR: A Breakthrough Method
In collaboration with Eli Lilly and the University of KwaZulu-Natal, the Livingston Group developed PEPSTAR, a “one pot” liquid phase method that isolates growing peptides using organic solvent nanofiltration (OSN). This process filters out reaction debris and isolates peptides without phase or material transfers between cycles.
A typical PEPSTAR cycle involves:
- Coupling the amino acid to a “nanostar” support
- Removing the Fmoc protecting group
- Quenching
- Filtering out reaction debris through a membrane to achieve “nanostar sieving”
The team successfully synthesized short peptides (5-10 amino acids) using PEPSTAR, achieving higher purity and reducing costs by half compared to the solid phase method.
The Future of PEPSTAR
Professor Andrew Livingston highlighted the potential of PEPSTAR to drive down the cost of peptide drugs, making them more accessible to patients. Researcher Jet Yeo added, “This novel approach offers not only a new paradigm for peptide synthesis but is also applicable across the synthesis of other high-precision polymers.”
PEPSTAR could be adapted for producing long peptides (over 20 amino acids) or proteins (over 50 amino acids) with further modifications. Its applications extend to the synthesis of high-precision polymers like oligonucleotides, polyesters, and polyethylene glycols, which are crucial in genetic testing, forensics, and medicine.
Reference
The research, “Liquid Phase Peptide Synthesis via One-Pot Nanostar Sieving (PEPSTAR)” by Jet Yeo et al., is available in Angewandte Chemie.
This work was supported by the Engineering and Physical Sciences Research Council (Grant Number: MO1486/X) and Eli Lilly and Company (Research Award Programme).
