This is important because such an approach enables them to shape peptides so they are more stable and have the desired properties, which can support the development of drugs and functional materials. The research was published in the international scientific journal Angewandte Chemie International Edition.
In nature, for example in proteins, what matters is not only what a molecule is made of, but also how it is “arranged” and folded, this often determines what it can do. That is why scientists, in addition to the usual 20 amino acids, also use additional, specially designed amino acids so they can “assemble” molecules with predictable properties. Such “new” amino acids are now essential in the development of modern drugs, substances that speed up chemical reactions, and new materials.
Why is peptide shape important?
Peptides are short chains of amino acids, and their biological activity largely depends on their three-dimensional shape. The same chemical composition can have a completely different effect if the molecule is folded in a different way. For this reason, scientists have been seeking reliable ways to control peptide conformation for decades.
One approach is the introduction of so-called noncanonical amino acids. These are building blocks that do not occur in natural proteins, but offer additional possibilities for shaping a molecule.
C-glycosyl amino acids are special amino acids to which a sugar is “attached” via a strong covalent bond. In nature, they occur as products of bacterial metabolism and show a broad spectrum of activity. Because this bond is difficult to break, such amino acids are often used in drug development to obtain more stable versions of sugar-containing molecules, and to make peptides last longer in the body and act more reliably. However, until now, very little was known about how incorporating such amino acids changes the way a peptide folds in space.
A limitation of existing synthetic approaches was that they allowed the addition of such sugar-containing amino acids only at one of the two ends of a peptide, or at special sites that had to be prepared in advance.
“In this research, we described a more practical method that makes it possible to insert sugar-containing amino acids at different positions within a peptide, not only at its ends,” explains Dr Barbara Bogović, the first author of the paper.
The scientists prepared four new amino acids with sugars, galactose, ribose, sorbose, and allose, and incorporated them into peptides in the laboratory step by step. This enabled them to clearly compare how the peptide’s shape is affected both by the type of sugar and by the position of the sugar within the chain. “When we carried out a detailed structural analysis, we found that each of these sugar-modified amino acids promotes a different way of folding of the peptide chain. A key role is played by networks of hydrogen bonds that form between the peptide backbone and the sugar groups,” explains Dr Ivanka Jerić, the corresponding author of the paper.
In other words, sugars do not serve only as “pendants” on a molecule, they actively participate in shaping its structure. By combining several such amino acids, it is possible to achieve strongly folded, stable, or, alternatively, extended peptide shapes, almost as if one were using a molecular alphabet to write three-dimensional structures.
These results show that the four new sugar-containing amino acids can “set” how a peptide will fold, so they can be used as new tools for creating better drugs, new materials, and more efficient chemical processes. The team behind this research brings together scientists from the Division of Organic Chemistry and Biochemistry and the NMR Centre at RBI. Alongside the first author, Dr Barbara Bogović, and Dr Ivanka Jerić, the team also includes Dr Ivana Colić, Dr Ivana Nikšić-Franjić, and Dr Vilko Smrečkij.
The research was funded by the Croatian Science Foundation through the project “Non-proteinogenic amino acids to increase the conformational diversity of peptides” (IP-2022-10-9617). Barbara Bogović’s work was supported under the Croatian Science Foundation programme “Young Researchers’ Career Development Project, training of new PhDs” (DOK-2021-02-5260).
