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Protection of the indole nucleus of tryptophan in solid-phase peptide synthesis with a dipeptide that can be cleaved rapidly at physiological pH
Stockholm University, Faculty of Science, Department of Neurochemistry.
Stockholm University, Faculty of Science, Department of Neurochemistry.
Stockholm University, Faculty of Science, Department of Neurochemistry.ORCID iD: 0000-0003-1003-6472
2011 (English)In: Tetrahedron Letters, ISSN 0040-4039, E-ISSN 1359-8562, Vol. 52, no 44, 5876-5879 p.Article in journal (Refereed) Published
Abstract [en]

The synthesis of a new derivative of tryptophan Fmoc-Trp(Boc-Sar-Sar)-OH is described. Fmoc-Trp(Boc-Sar-Sar)-OH is introduced into peptides by solid-phase peptide synthesis and during treatment with TFA at the end of the synthesis, the Boc group is cleaved and the peptide is obtained with the indole nucleus modified with the sarcosinyl-sarcosinyl (Sar-Sar) moiety. This modification will introduce a cationic charge that improves the solubility of the peptide during HPLC purification. The Sar-Sar moiety is cleaved upon exposure to physiological pH. The Boc-Sar-Sar group might, therefore, also find use in the design of pro-drugs of indole-containing compounds.

Place, publisher, year, edition, pages
2011. Vol. 52, no 44, 5876-5879 p.
Keyword [en]
Solid-phase peptide synthesis, Protecting group, Cyclization-activated prodrugs, Tryptophan, Fmoc amino acids
National Category
Natural Sciences
Research subject
Neurochemistry with Molecular Neurobiology
Identifiers
URN: urn:nbn:se:su:diva-69881DOI: 10.1016/j.tetlet.2011.08.172ISI: 000296168300039OAI: oai:DiVA.org:su-69881DiVA: diva2:479788
Note
authorCount :3Available from: 2012-01-18 Created: 2012-01-15 Last updated: 2017-12-08Bibliographically approved
In thesis
1. Development of antimicrobial peptides: Methodological aspects, design, synthesis and evaluation of a new class of antimicrobial peptides
Open this publication in new window or tab >>Development of antimicrobial peptides: Methodological aspects, design, synthesis and evaluation of a new class of antimicrobial peptides
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

A new protective group for the indole nitrogen of the amino acid tryptophan, the Boc-sarcosinoyl-sarcosinolyl (Boc-Sar-Sar) is described. This protective group shows good stability to the reaction conditions used in solid phase peptide synthesis and can be incorporated into the peptide as Fmoc-Trp(Boc-Sar-Sar)-OH. When the peptide is cleaved from the resin with trifluororoactetic acid, the Boc group is simultaneously cleaved and the N-terminal nitrogen in the Sar-Sar group is exposed. At low pH this amino group is protonated and thereby the peptide will have higher solubility in aqueous solution. High solubility of the peptide is an important factor for the purification of peptides with reversed phase HPLC. During HPLC purification, the protonated Sar-Sar group will remain on the peptide. When the purified peptide is exposed to physiological pH, the Sar-Sar group will be cleaved and the peptide will be obtained in its fully deprotected form.

Gramicidin A (GA) is an extremely hydrophobic peptide with four tryptophan residues. To improve the solubility of GA, Fmoc-Trp(Boc-Sar-Sar)-OH was used in the solid phase synthesis of GA resulting in (H-Sar-Sar)4-GA. When this peptide was exposed to physiological pH native GA was formed.

A new class of antimicrobial peptides, represented by the enantiomers; cyclo[D-Tle-D-Lys-D-Tle-L-Ala-D-Tle-L-Ala-D-Tle-L-Ala] and cyclo[L-Tle-L-Lys-L-Tle-D-Ala-L-Tle-D-Ala-L-Tle-D-Ala] is described. Neither of the two peptides shows any significant antimicrobial activity against Bacillus megaterium. However, when both peptides are present during the experiment a potent antimicrobial activity with an IC50 value of 2 µM could be observed. The peptides also show low hemolytic activity with an HC50 value of 316 µM. The synergistic mode of action of these peptides is dependent on the presence of both enantiomers. Circumstantial evidences indicate that the antimicrobial effect is the result of formation of peptide nanotubes within the bacterial membrane.

It is also shown that the cyclic peptides described above can be modified at the lysine residue with three arginine residues in which the N-terminus is acylated with a short fatty acid. Togheter these peptides show a synergistic mode of action against Staphylococcus aureus resulting in a MIC value of 9 µM.

Place, publisher, year, edition, pages
Stockholm: Department of Neurochemistry, Stockholm University, 2012. 75 p.
National Category
Natural Sciences
Research subject
Neurochemistry with Molecular Neurobiology
Identifiers
urn:nbn:se:su:diva-73366 (URN)978-91-7447-459-6 (ISBN)
Public defence
2012-03-30, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 16 B, Stockholm, 10:00 (English)
Opponent
Supervisors
Note

At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 2: Submitted. Paper 4: Manuscript.

Available from: 2012-03-08 Created: 2012-02-21 Last updated: 2015-03-06Bibliographically approved

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