Dr Liming Zhang, professor in the Department of Chemistry and Biochemistry at the University of California Santa Barbara, is leading research that could widen the design space for peptide based drugs and materials. In a study published in the Journal of the American Chemical Society, Zhang and his colleagues describe an efficient method for synthesizing non natural amino acids that can be used directly in peptide construction. The approach reduces the number of synthetic steps typically required and aligns closely with established peptide manufacturing workflows.
Kohnke, P., & Zhang, L. (2026). Expedient Synthesis of N -Protected/ C -Activated Unnatural Amino Acids for Direct Peptide Synthesis. Journal of the American Chemical Society, 148(5), 5615–5622. https://doi.org/10.1021/jacs.5c20374
Peptides have become an important class of therapeutics over the past several decades. They bridge the gap between small molecules and large biologics, offering high specificity while remaining accessible to chemical synthesis. Drugs derived from peptide sequences are now used to treat diabetes, metabolic disorders and other chronic conditions. Their success has often depended on structural modifications that improve stability and receptor binding, many of which involve non natural amino acids.
Dr Liming Zhang, from University of California Santa Barbara stated,
“The key advantage is that these amino acids come out of the process already in a form that can be used directly to make peptides, without extra modification steps. Compared to existing approaches, this is one of the most straightforward and broadly useful methods reported so far.”
In living organisms, proteins and peptides are built from a limited set of amino acids. Twenty canonical amino acids are encoded in DNA, with two additional ones incorporated through specialized biological pathways. Although this restricted set is sufficient for biological function, it limits the chemical diversity available to researchers. Expanding beyond these naturally occurring building blocks enables chemists to fine tune molecular shape, rigidity and resistance to enzymatic degradation.
Producing non natural amino acids has historically been challenging. Existing methods can require multiple protection and deprotection steps, specialized reagents or labor intensive purification to separate mirror image forms. These hurdles increase cost and complexity, which in turn limit the accessibility of modified residues to laboratories without dedicated synthetic chemistry expertise.
The Zhang laboratory addressed these limitations by developing a two step sequence based on gold catalysis. Starting from inexpensive and widely available chemical precursors, the team constructs amino acid derivatives that are already configured for peptide assembly. The amino group is protected in a way that allows selective activation when needed, while the carboxylic acid component is pre activated for coupling. This design minimizes additional manipulations during peptide synthesis.
A notable feature of the process is its stereoselectivity. Amino acids exist as mirror image structures, but biological systems predominantly utilize one orientation. Producing the correct configuration during synthesis avoids the need for later separation and ensures compatibility with biological targets. The reported method achieves high control over this aspect, yielding products suitable for immediate incorporation into peptide chains.
To build peptides, the team uses solid phase synthesis on a resin scaffold, a method widely employed in both research and industry. In this approach, the growing peptide is anchored to an insoluble support, allowing excess reagents to be washed away after each coupling reaction. The cycle repeats until the full sequence is assembled, after which the peptide is cleaved from the resin. Because the newly synthesized amino acids are designed to fit directly into this established process, the method can be adopted without significant procedural changes.
The ability to access a broader set of amino acids has practical consequences for drug design. Natural peptides are often rapidly degraded by enzymes in the body. Introducing non natural residues can protect vulnerable bonds, impose conformational constraints or enhance binding affinity to specific receptors. Such modifications can improve half life and reduce dosing frequency, key considerations in pharmaceutical development.
Beyond therapeutics, non natural amino acids also have applications in materials science. Peptide based materials are being explored for self assembling nanostructures, responsive surfaces and biomedical scaffolds. Expanding the range of available building blocks increases the structural and functional diversity of these systems. A streamlined route to modified amino acids lowers the barrier to experimentation in these areas.
The research community has responded with interest because the method addresses both chemical and practical challenges. Previous strategies often worked only for a narrow class of amino acids or required extensive downstream adjustments before integration into peptide synthesis. By contrast, the gold catalyzed approach appears adaptable and designed with process compatibility in mind.
There are still considerations for scaling and broader deployment. Gold is an effective catalyst but carries cost implications, so recycling strategies and process optimization will be important if the chemistry is translated beyond laboratory scale. In addition, the biological performance of peptides incorporating these newly synthesized residues must be validated in specific therapeutic contexts. Each modification can influence folding behavior, target interaction and metabolic stability.
Dr Zhang’s group is now investigating ways to automate the process. Integrating the synthesis of non natural amino acids into automated peptide synthesizers would make the technology accessible to researchers outside of synthetic chemistry. Collaborative efforts with pharmaceutical and materials science teams are also under consideration, aimed at applying the methodology to real world challenges.
From an engineering perspective, the significance of the work lies in how it connects molecular innovation with manufacturing practicality. By designing amino acid derivatives that are already configured for standard peptide assembly, the team has reduced friction between discovery and application. The approach does not replace existing methods, but it provides a streamlined alternative that expands the chemical palette available to researchers.
As peptide therapeutics continue to grow as a drug class and peptide based materials gain traction in advanced applications, access to diverse and precisely defined building blocks will become increasingly important. The contribution from the University of California Santa Barbara adds a practical tool to that effort, enabling scientists to explore new molecular architectures with fewer synthetic obstacles.
Adrian graduated with a Masters Degree (1st Class Honours) in Chemical Engineering from Chester University along with Harris. His master’s research aimed to develop a standardadised clean water oxygenation transfer procedure to test bubble diffusers that are currently used in the wastewater industry commercial market. He has also undergone placments in both US and China primarely focused within the R&D department and is an associate member of the Institute of Chemical Engineers (IChemE).
