Abstract
This article reports on the design and characteristics of substrate mimetics in protease-catalyzed reactions. Firstly, the basis of protease-catalyzed peptide synthesis and the general advantages of substrate mimetics over common acyl donor components are described. The binding behavior of these artificial substrates and the mechanism of catalysis are further discussed on the basis of hydrolysis, acyl transfer, protein-ligand docking, and molecular dynamics studies on the trypsin model. The general validity of the substrate mimetic concept is illustrated by the expansion of this strategy to trypsin-like, glutamic acid-specific, and hydrophobic amino acid-specific proteases. Finally, opportunities for the combination of the substrate mimetic strategy with the chemical solid-phase peptide synthesis and the use of substrate mimetics for non-peptide organic amide synthesis are presented.
Highlights
In addition to the natural function of enzymes, their capability of catalyzing selective transformations makes these biomolecules useful catalysts in synthetic organic chemistry
The synthetic use of these biocatalytic approaches would indisputably facilitate the chemical synthesis of peptides which often suffers from problems such as racemization, time-consuming sidechain protection and deprotection strategies, poor solubility of protected peptide fragments, and length limitation
A further important advantage of substrate mimetic-mediated synthesis reactions results from the fact that the C-terminal amino acid residue to be coupled does not function as a specificity determining moiety
Summary
In addition to the natural function of enzymes, their capability of catalyzing selective transformations makes these biomolecules useful catalysts in synthetic organic chemistry. The amidase activity of proteases which may cause undesirable proteolytic cleavages of the peptide chain formed and the limited substrate specificities of these enzymes which restricts the amino acid residues accepted for coupling are the major disadvantages of this approach.
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