Iron catalysts diversify amino acids and peptides

To create peptides with diverse types of bioactivity, microorganisms use multienzyme complexes called nonribosomal peptide synthetases (NRPSs). For example, bacteria make the antibiotic vancomycin this way. Iron-based enzymes in NRPSs oxidize and modify amino acids both before and after the complexes assemble the amino acids into peptides.

A new technique enables chemists to diversify amino acids and peptides the way that NRPSs do. The approach, its developers say, could make it easier to discover new peptide-based therapeutics, dozens of which are already on the market or in testing.

Chemists aren’t as good at diversifying peptides as microbes are. Researchers often must synthesize peptides with modified amino acids from scratch, a laborious and time-consuming process. There are a few ways to oxidize amino acids to functionalize the molecules, but these techniques are frequently difficult, sometimes alter amino acid stereochemistry, and have limited ability to modify amino acids already in peptides.

M. Christina White and coworkers at the University of Illinois, Urbana-Champaign, in collaboration with chemists at Pfizer, now find that two previously discovered iron-based catalysts called Fe(PDP) and Fe(CF₃PDP) can oxidize specific amino acids, either alone or in peptides, while maintaining native stereochemistry (Nature 2016, DOI: 10.1038/nature18941).

Working with proline by itself or in peptides, they used the iron catalysts to hydroxylate the amino acid at the 5-position on its ring and then used other reactions to further modify the resulting 5-hydroxyproline intermediate. They used that approach to convert proline into 21 unnatural amino acids and to diversify a proline-containing tripeptide into eight modified tripeptides.

“Peptides are very much in vogue in the pharma and biotech world as leads for new small-molecule therapeutics, so this elegant work is relevant to contemporary drug design,” comments Dalibor Sames of Columbia University.

“Time will tell how generalizable this sort of platform will be,” says David R. Spring of the University of Cambridge. Nevertheless, the technique is “a remarkable development,” and the ability to site-selectively oxidize proline in complex peptides “is very exciting for chemists,” he says.