Oxidizing Amino Acids and Peptides Could Lead to New Drugs

Researchers in a recent study turned amino acids into new forms using 2 iron-containing small-molecule catalysts. These amino acids even kept their chirality when changed.

“This allows us to take 1 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,” said lead researcher M. Christina White, PhD. “It also expands the pool of unnatural chiral amino acids that are available to researchers to make new structures.”

Chiral molecules can have different spatial arrangements of their atoms (stereochemistry), and are known as “right-hand” and “left-hand” versions that can behave differently than the other version.

“That's why having things with defined stereochemistry can be very important for drug discovery," Dr White said. “It can be that a molecule of 1 handedness has fantastic physiological properties, but the same molecule with the opposite handedness could have very detrimental properties.”

In a study published by Nature, researchers used 2 iron catalysts and were able to create 21 amino acid structures from 4 chiral amino acids (proline, leucine, valine, and norvaline). All amino acids that were created maintained their handedness.

Oxidative amino acid modification is routine in nature, and creates various peptides with various properties, according to the study. There are 20 naturally occurring amino acids, which are then altered by carbon-hydrogen oxidation reactions that change their shape, or create additional functional groups.

Reactions in nature are usually caused by iron-containing enzymes. However, these enzymes are difficult to control in the laboratory, the researchers wrote.

“These enzymes are also very specific. They are usually tailored to 1 amino acid or 1 peptide structure,” Dr White said. “Two big advantages to the small-molecule catalysts we've developed are that they are very general -- they can work on many different amino acid and peptide structures -- and they are very easy to use. They can create great diversity initiated by 1 simple carbon-hydrogen oxidation reaction.”

Although the catalysts are general about what substrate they oxidize, and they are specific about the carbon-hydrogen bonds they cut, according to the study. The catalysts can target a specific spot on an amino acid even when they are part of a large chain.

Researchers were able to create 8 different peptides with unnatural amino acids from 1 proline-containing peptide chain.

“This is powerful because right now, if you want to make those 8 different peptides, you would have to do 8 different syntheses,” Dr White concluded. “And before you could do that, you'd have to synthesize the individual unnatural amino acid components. With our method, you can build 1 peptide out of bulk chemicals and use 1 carbon-hydrogen oxidation reaction, coupled with a reaction to add a functional group, to produce 8 new peptides all with retained handedness.”