Iron catalysts diversify amino acids and peptides | August 4, 2016 Issue - Vol. 94 Issue 32 | Chemical & Engineering News
Volume 94 Issue 32 | p. 7 | News of The Week
Issue Date: August 8, 2016 | Web Date: August 4, 2016

Iron catalysts diversify amino acids and peptides

New method mimics peptide-synthesis enzyme complexes found in microorganisms
Department: Science & Technology
News Channels: Organic SCENE
Keywords: catalysis, hydroxylation, iron, catalysis, proline, amino acid, peptide
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An iron catalyst hydroxylates proline, alone or in a peptide, to a 5-hydroxyproline intermediate that can then be functionalized. Red shows modifications, EDG = electron-donating group, R = 4-nitrophenylsulfonyl or peptide, R´ = methoxy or peptide, and X = carboxyl, amine, alcohol, or olefin.
Reaction scheme shows that iron catalyst hydroxylates proline (4-nitrophenylsulfonyl- and methoxy-protected, or in a peptide) to a 5-hydroxyproline intermediate that is then diversified.
 
An iron catalyst hydroxylates proline, alone or in a peptide, to a 5-hydroxyproline intermediate that can then be functionalized. Red shows modifications, EDG = electron-donating group, R = 4-nitrophenylsulfonyl or peptide, R´ = methoxy or peptide, and X = carboxyl, amine, alcohol, or olefin.

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.

 
Chemical & Engineering News
ISSN 0009-2347
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Comments
Dr Jignesh Patel (Thu Aug 04 23:55:12 EDT 2016)
One example of Pipecolic acid, wonder why they have not elaborated on this six membered Amino acid, which is more useful. Or may be a more exciting results further due from this extra ordinary group.

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