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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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July 16, 2014

An Easy Way to Make Cyclic Peptides

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Posted by Derek

If you ever find yourself needing to make large cyclic peptides, you now have a new option. This paper in Organic Letters describes a particularly clean way to do it: let glutathione-S-transferase (GST) do the work for you. Bradley Pentelute's group at MIT reports that if your protein has a glutathione attached at one end, and a pentafluoroaryl Cys at the other, that GST will step in and promote the nucleophilic aromatic substitution reaction to close the two ends together.
cyclic%20GST.jpg
This is an application of their earlier work on the uncatalyzed reaction and on the use of GST for ligation.. Remarkably, the GST method seems to product very high yields of cyclic peptides up to at least 40 residues, and at reasonable concentration (10 mM) of the starting material, under aqueous conditions. Cyclic peptides themselves are interesting beasts, often showing unusual properties compared to the regular variety, and this method look as it will provide plenty more of them for study.

Comments (7) + TrackBacks (0) | Category: Chemical Biology | Chemical News


COMMENTS

1. Anonymous on July 16, 2014 1:25 PM writes...

My big question is:

How does the linking S-ArF-S group look from a pharmacological and toxicological perspective?

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2. newnickname on July 16, 2014 2:54 PM writes...

@1: The dithiophenyl can undergo further substitution, but the it's not the greatest reaction. Q.v., Russian Journal of Organic Chemistry (2005), 41(12), 1782-1786. Russian Journal of Organic Chemistry (2000), 36(6), 820-825.

Of course, it doesn't have to be a quantitative displacement to produce an undesired side effect in vivo.

(I haven't read the Pentelute paper: maybe they put it through some tests and it's OK.)

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3. Anonymous on July 16, 2014 3:36 PM writes...

And what about potential oxidation to toxic metabolites?

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4. gippgig on July 16, 2014 6:09 PM writes...

How specific is the reaction for the para position of the perfluoroaryl? Would it work with perfluoroaryl serine (O instead of S)?
Does the perfluoroaryl have to be at the end of the peptide? Could this be used to make stapled peptides?

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5. dr z on July 16, 2014 6:27 PM writes...

this is definitely interesting methodology, esp the high concentration and large macrocycle aspects.

can you add glutathione enzymatically to the n-terminus of a peptide? otherwise this method is only restricted to synthetic peptides, and so there are many options available. methods which can be applied to recombinant peptides as well are much more powerful

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6. Anonymous on July 17, 2014 10:00 AM writes...


@1, @3 The perfluoroaromatic group, once installed, is fairly unreactive. It is stable over long periods in water / acid / base. Things might be different in the liver, but I doubt much would happen

@4 Specific for S (under particular pH). The reaction needs a strong nucleophile, like thiolate. O- would work, but then you'd be outside of normal pH ranges. As for para-specific, the best guess at a mechanism involves resonance activation at para position, and that is the only observed product. See the JACS 2013 paper.

Also, this reaction was first used for stapled peptides, then later for labeling with GST. Again, see JACS 2013.

@5 you are right, the need for the γ-glutamic acid means that this only works for synthetic peptides.

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7. Name on July 17, 2014 3:39 PM writes...

somebody is an author on the paper!! ^^^^

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