The metabolism of cells and structure living organisms is essential for the development of new medicine and diagnostics. The availability of chemical tools that permit scientists to edit biomolecules, like proteins, with the atom-level resolution has enormously contributed to the progress of chemical biology.
Proteins are macromolecules constructed from a set of twenty chemically completely different amino acids. One key method to modify proteins is to react with the sulfur atom in the amino acid cysteine. However, current methods are still problematic by way of effectivity, selectivity, and stability of the final product (the “adduct”).
Institute of Chemical Sciences and Engineering of EPFL have developed a new methodology for modifying cysteines on peptides and proteins. The strategy uses a group of highly reactive organic molecules, the ethynyl benziodoxol ones (EBXs). What makes EBXs extremely reactive is that they contain an iodine atom certain to three substituent groups. This non-natural situation results in high reactivity in these so-known as “hypervalent iodine” reagents.
For the first time, the researchers had been in a position to generate a simple biomolecule-EBX adduct whereas protecting their reactive iodine group in the final molecule. The response might be simply performed by a non-expert beneath normal physiological conditions.
The end product is protein-hypervalent iodine reagent chimeras that may act as dual attachment points for two new chemical groups, opening up new possibilities for the research of biological processes.
The investigators demonstrated the potential of the method by introducing a diverse set of chemical groups into biomolecules. For instance, the scientists used the dual handle to connect a fluorescent dye and a photo protecting group into a neuropeptide simultaneously. Combining them improves the dye’s photostability, and permits high-resolution, single-molecule imaging of molecular interactions.
Beyond peptides, they further transformed small proteins, and even large protein-DNA complexes, so-referred to as nucleosomes. As nucleosomes organize the genome, specifying them with fluorescent dyes may help observe them decipher how nature regulates gene expression.