Ozempic has garnered attention for its efficacy in treating obesity and diabetes, yet it is merely one in an expanding class of drugs known as peptide therapeutics. These sit between small molecules, such as aspirin, and biologics like antibodies. A research team at UC Santa Barbara has developed a technique for the efficient synthesis of non-natural amino acids, a development detailed in the Journal of the American Chemical Society. This method is anticipated to significantly advance peptide research by providing scientists with access to amino acids beyond the 22 found in nature.
The technique’s primary advantage is that these amino acids emerge from the process ready for direct use in peptide creation, eliminating additional modification steps. Phil Kohnke, the first author and a doctoral student in Liming Zhang’s lab, emphasised that this method is among the most straightforward and broadly applicable reported to date.
Amino acids, the building blocks of proteins, are fundamental biological molecules. Peptides, which consist of 10 to 50 amino acids, are simpler than proteins, which are longer and more complex. Nature uses only 22 amino acids to construct proteins, 20 of which are coded in DNA, with two produced by other mechanisms. While natural amino acids are produced cheaply, the new method facilitates the chemical synthesis of non-natural amino acids, which can be directly used for peptide synthesis.
The newly published paper outlines a two-step technique for synthesising and binding amino acids into peptides using a resin scaffold. Gold catalysis is utilised to create amino acids from inexpensive, readily available chemicals. The approach is highly stereoselective, producing amino acids with specific handedness rather than a mix of right- and left-handed forms. The process requires exposing and priming reactive sites, ensuring the correct sequence for peptide synthesis. The method simplifies peptide purification, allowing molecules to be cleaved from the scaffold and easily washed off.
Access to a broader range of amino acids opens new possibilities for biochemists, medical researchers, and materials scientists. Many existing methods for producing non-natural amino acids are complex, time-consuming, or impractical. The new technique addresses these challenges, producing amino acids that are immediately useful for peptide synthesis.
Zhang is particularly interested in developing new peptide therapeutics. Peptides have been used in over 80 drugs worldwide since insulin’s synthesis in the 1920s. Natural peptides, while effective, are fragile and susceptible to enzymatic degradation. Incorporating non-natural amino acids can enhance peptide stability and efficacy. Ozempic, for example, contains a non-natural amino acid and a fatty acid side chain.
The Zhang lab is working to automate this process, aiming to make non-natural amino acids readily available to non-chemists. They seek collaboration with other research teams to enhance the technique’s accessibility for drug development and materials research.
