Too close for comfort: cleaving amides at neutral pH

The track record of man-made enzyme mimetics is not impressive. I previously commented that, time and again, we get beaten by nature’s enzymes in terms of catalytic efficiency. If we consider hydrolases, it is all about the spatiotemporal relationship between their catalytic amino acid residues and the peptide bond that is being cleaved. Things happen at the right place and at the right time. There have been many attempts to prepare synthetic hydrolase mimetics that were claimed to be close to their natural congeners in terms of catalytic efficiency. None of these examples have withstood the test of time: each was shown to be the product of sample contamination with some hydrolase. However, there is one really excellent example from the past that employs spatiotemporal arguments and proves that, once proximity has been secured, amazing efficiency for activating strong bonds can be achieved. A classic JACS paper by Fred Menger from 1988 describes a very curious amide that hydrolyzes fast at neutral pH with a t1/2 of 8 minutes, which corresponds to an effective molarity of at least 10l2M. Given the strength of the prolyl amide linkage, this classic example is remarkable.


Is there an immediate use for something like this? It is difficult to think of an application, but there is a lesson here to those of us who are driven by small peptides that fold into compact shapes. First and foremost, I refer to cyclic peptides and peptidomimetics. The question about cyclic peptide stability has been raised time and again, yet one often assumes that it is all about stability against proteolysis. The proteolytic degradation is difficult for a cyclic peptide (to the extent that it is not even worth pointing out this feature as a cool attribute of cyclic peptides – it is obvious that they do not adopt the necessary extended conformations. Here is a great reference that discusses this property, by the way: But chemical stability is another issue and I would predict that there are cases where amide bonds in complex macrocycles are unstable for reasons that operate in the case described by Menger 25 years ago.

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