Effect of Methionine Sulfoxide on the Synthesis and Purification of Aggregation‐Prone Peptides

Abstract

A two-step synthesis for methionine-containing hydrophobic and/or aggregation-prone peptides is presented that takes advantage of the reversibility of methionine oxidation. The use of polar methionine sulfoxide as a building block in solid-phase peptide synthesis improves the synthesis quality and yields the crude peptide, with significantly improved solubility compared to the reduced species. This facilitates the otherwise often laborious peptide purification by high-performance liquid chromatography. The subsequent reduction proceeds quantitatively. This approach has been optimised with the methioninerich Tar-DNA-binding protein 43 (307-347), but is also more generally applicable, as demonstrated by the syntheses of human calcitonin and two aggregation-prone peptides from the human prion protein.

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“…The oxidation of l ‐methionine to the corresponding sulfoxide (Figure 1B), previously already used for LSC‐PM applications, [17] was chosen as a benchmark reaction, since having water as a solvent is easily scalable and safe to operate outdoors. Interestingly, methionine sulfoxide has many biochemical applications, [25] including in studies of cell ageing and oxidative stress, in peptide sciences, [26] and in material sciences and organic synthesis [27] . For example, it can increase the permeability of oxygen in water through a polypeptide film, crucial for contact lenses [28,29] .…”

“…Interestingly, methionine sulfoxide has many biochemical applications, [25] including in studies of cell ageing and oxidative stress, in peptide sciences, [26] and in material sciences and organic synthesis. [27] For example, it can increase the permeability of oxygen in water through a polypeptide film, crucial for contact lenses. [ 28 , 29 ] Traditionally, the oxidation of sulfides is done with peroxides, but this method often suffers from over‐oxidation to the corresponding sulfones.…”

The CSY-protecting group in the microwave-assisted synthesis of aggregation-prone peptides

“…As a pleasant side effect, the polar CSY group increases the solubility of the synthesized peptide and counteracts aggregation on a solid support, an effect also observed when using methionine sulfoxide building blocks in peptide synthesis. 10 Encouraged by this report, we intended to apply this new Asp building block to the synthesis of b-sheet peptides (sequences Table 1) that contain Asp in their sequences and that we could not previously access using standard peptide synthesis protocols. Peptides 1 and 2 are derived from WW domains that are involved in neuronal signal transduction and are linked to Alzheimer-dementia 11 and Golabi-Ito-Hall syndrome, 12 respectively.…”

“…As a pleasant side effect, the polar CSY group increases the solubility of the synthesized peptide and counteracts aggregation on a solid support, an effect also observed when using methionine sulfoxide building blocks in peptide synthesis. 10 …”

Untersuchungen zur Aggregation des ALS-relevanten TDP-43(307-347)

“…[63] Die Oxidation von Methionin kann darüber hinaus Transkriptionsfaktoren aktivieren, wie es anhand des Hypochlorit-responsiven Transkriptionsfaktor (HypT) gezeigt werden konnte. [64] In der Peptidchemie dient Methioninsulfoxid unter anderem als Schutzgruppe, die erstmals 1961 von ISELIN eingesetzt wurde, [65] und zur Erhöhung der Löslichkeit in der SPPS [66] oder in chemischen Ligationen genutzt wird. [67] Eine weitere Anwendung ist die Untersuchung des Einflusses von Oxidation, zum Beispiel verursacht durch oxidativen Stress, auf die Sekundärstruktur, die Toxizität und die Aggregation von Peptiden und Proteinen.…”