For medicinal chemists, making tweaks to peptide structures is key to developing new drug candidates. Now, researchers have demonstrated that two iron-containing small-molecule catalysts can help turn certain types of amino acids—the building blocks of peptides and proteins—into an array of potential new forms, even when part of a larger peptide, while preserving a crucial aspect of their chemistry: chirality, or “handedness.”
Led by Illinois chemistry professor M. Christina White, researchers from the University of Illinois at Urbana-Champaign in collaboration with researchers at Pfizer Global Research and Development detailed the new reactivity of the catalysts in the journal Nature.
“This allows us to take one amino acid structure and convert it into many different structures that represent different functionalities, which could ultimately lead to different biological and physical properties of the peptide,” White said. “It also expands the pool of unnatural chiral amino acids that are available to researchers to make new structures.”
A main advantage to the catalysts, which oxidize bonds between carbon and hydrogen, is that they preserve the amino acid’s sense of chirality. Chiral molecules can have more than one spatial arrangement of their atoms, or stereochemistry, sometimes known as “right-hand” and “left-hand” versions. Although they share the same chemical formula, molecules of opposite handedness can behave very differently in the body. For example, L-DOPA is a drug used to treat Parkinson’s disease, whereas its mirror version, D-DOPA, is biologically inactive.
“That’s why having things with defined stereochemistry can be very important for drug discovery,” White said. “It can be that a molecule of one handedness has fantastic physiological properties, but the same molecule with the opposite handedness could have very detrimental properties.”
Using the two iron catalysts, the researchers were able to take four chiral amino acids – proline, leucine, valine and norvaline—and diversify them into 21 different amino acid structures while preserving their handedness. The new structures can be used to create modified versions of existing peptides or to build entirely new structures.
Such oxidative amino acid modification is performed routinely in nature to make a variety of different peptides with different properties. Twenty common amino acids exist in nature, but are altered by carbon-hydrogen oxidation reactions to change their shape or add functional groups such as alcohols or carboxylic acids. These reactions are typically catalyzed by iron-containing enzymes. However, the enzymes are very difficult to work with in a laboratory setting, White said.