Dataset Information

General lack of structural characterization of chemically synthesized long peptides.

ABSTRACT: Many peptide chemistry scientists have been reporting extremely interesting work on the basis of chemical peptides for which the only characterization was their purity, mass, and biological activity. It seems slightly overenthusiastic, as many of these structures should be thoroughly characterized first to demonstrate the uniqueness of the structure, as opposed to the uniqueness of the sequence. Among the peptides of identical sequences in the final chemical preparation, what amount of well-folded peptide supports the measured activity? The activity of a peptide preparation cannot prove the purity of the desired peptide. Therefore, greater care should be taken in characterizing peptides, particularly those coming from chemical synthesis. At a time when the pharmaceutical industry is changing its paradigm by moving substantially from small molecules to biologics to better serve patients' needs, it is important to understand the limitations of the descriptions of these products and to start to apply the same "good laboratory practices" to our peptide research. Here, we attempt to delineate how synthetic peptides are described and characterized and what will be needed to describe them in regards to how they are well-folded and homogeneous in their tertiary structure. Older studies were done when the tools were not yet discovered, but more recent publications are still lacking proper descriptions of these peptides. Modern tools of analysis are capable of segregating folded and unfolded peptides, even if the preparation is biologically active.

SUBMITTER: Boutin JA

PROVIDER: S-EPMC6459998 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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General lack of structural characterization of chemically synthesized long peptides.

Boutin Jean A JA Tartar André L AL van Dorsselaer Alain A Vaudry Hubert H

Protein science : a publication of the Protein Society 20190325 5

Many peptide chemistry scientists have been reporting extremely interesting work on the basis of chemical peptides for which the only characterization was their purity, mass, and biological activity. It seems slightly overenthusiastic, as many of these structures should be thoroughly characterized first to demonstrate the uniqueness of the structure, as opposed to the uniqueness of the sequence. Among the peptides of identical sequences in the final chemical preparation, what amount of well-fold ...[more]

PMID: 30851143

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Project description:The methylglyoxal-derived hydroimidazolones (MG-Hs) comprise the most prevalent class of non-enzymatic, post-translational modifications of protein arginine residues found in nature. These adducts form spontaneously in the human body, and are also present at high levels in the human diet. Despite numerous lines of evidence suggesting that MG-H-arginine adducts play critical roles in both healthy and disease physiology in humans, detailed studies of these molecules have been hindered by a lack of general synthetic strategies for their preparation in chemically homogeneous form, and on scales sufficient to enable detailed biochemical and cellular investigations. To address this limitation, we have developed efficient, multigram-scale syntheses of all MG-H-amino acid building blocks, suitably protected for solid-phase peptide synthesis, in 2-3 steps starting from inexpensive, readily available starting materials. Thus, MG-H derivatives were readily incorporated into oligopeptides site-specifically using standard solid-phase peptide synthesis. Access to synthetic MG-H-peptide adducts has enabled detailed investigations, which have revealed a series of novel and unexpected findings. First, one of the three MG-H isomers, MG-H3, was found to possess potent, pH-dependent antioxidant properties in biochemical and cellular assays intended to replicate redox processes that occur in vivo. Computational and mechanistic studies suggest that MG-H3-containing constructs are capable of participating in mechanistically distinct H-atom-transfer and single-electron-transfer oxidation processes. Notably, the product of MG-H3 oxidation was unexpectedly observed to disassemble into the fully unmodified arginine residue and pyruvate in aqueous solution. We believe these observations provide insight into the role(s) of MG-H-protein adducts in human physiology, and expect the synthetic reagents reported herein to enable investigations into non-enzymatic protein regulation at an unprecedented level of detail.

Dataset Information

General lack of structural characterization of chemically synthesized long peptides.

Publications

General lack of structural characterization of chemically synthesized long peptides.

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