Discovering new biological targets is a critical part of our ongoing battle against diseases. Over the years, scientists have made impressive progress toward the understanding of biological systems and have identified many novel targets—the structural diversity of which requires a broad range of therapeutic agents.
“Small synthetic molecules are still key players, but biomolecules such as peptides, proteins, and oligonucleotides have become an important area of research,” says senior author Jérôme Waser of EPFL.
Of particular interest are peptides. In 2015, about 140 peptides were evaluated in clinical trials. However, peptides are often unstable in the blood and cannot permeate cells well, both of which diminish their potential use as drugs.
One solution to this problem is chemically modifying the natural structure of peptides—a process called “functionalization.” A molecule is functionalized by adding chemical groups to it, thus endowing it with new functions, capabilities, or properties, such as enhanced stability in the human body.
However, functionalization of peptides is difficult due to their complex structure. “The main reason is the lack of selectivity when you try to modify a peptide: it contains many positions that react with chemicals, resulting in useless mixtures,” Waser explains. “Therefore, methods enabling selective functionalization of a single position in peptides are actively sought-after to access more efficient and stable peptide-based drugs.”
This is what Waser's lab achieved in a study published today in Angewandte Chemie. Using EBX reagents—a class of very reactive organic compounds that the team developed—the researchers converted the C-terminal carboxylic acid of peptides into a carbon–carbon triple bond called an alkyne. The alkyne moiety is a very valuable functional group that can be used to further modify the peptides. It has been used extensively in drug discovery, material sciences, and chemical biology.
To make the peptides react with the EBX reagents, the scientists used “photoredox catalysis,” a process in which visible light is absorbed by the catalyst, which then selectively activates one bond in the reacting molecules.
“Using light as a renewable energy source to perform organic reactions allows a temporal and spatial resolution with very mild reaction conditions,” Waser says.
With their new method, the scientists were able to obtain derivatives from the valuable bioactive peptide GRGDNP that blocks cells from attaching to fibronectin, an important process in the vasodilatation of blood vessels, which could be very useful in the study of cardiovascular disease.
Image: Sunlight experiment. The reactions can be performed using the light from the sun in a simple glass flask. Image courtesy of J. Waser/EPFL.