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Chemistry and folding of photomodulable peptides: stilbene and thioaurone-type candidates for conformational switches
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry. Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
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2008 (English)In: Organic and biomolecular chemistry, ISSN 1477-0520, E-ISSN 1477-0539, Vol. 6, no 23, 4356-4373 p.Article in journal (Refereed) Published
Abstract [en]

Optimized synthetic strategies for the preparation of photoswitchable molecular scaffolds based on stilbene or on thioaurone chromophores and their conformationally directing properties, as studied by computations and by NMR spectroscopy, are addressed. For the stilbene peptidomimetics 1, 2 and 3, the length of connecting linkers between the chromophore and the peptide strands was varied, resulting in photochromic dipeptidomimetics with various flexibility. Building blocks of higher rigidity, based on para-substituted thioaurone ( 4 and 6) and meta-substituted thioaurone chromophores ( 5 and 7) are shown to have a stronger conformationally directing effect. Design, synthesis, theoretical and experimental conformational analyses are presented.

Place, publisher, year, edition, pages
2008. Vol. 6, no 23, 4356-4373 p.
National Category
Pharmaceutical Sciences Chemical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-97699DOI: 10.1039/b812001cISI: 000261744800012PubMedID: 19005595OAI: oai:DiVA.org:uu-97699DiVA: diva2:172739
Available from: 2008-11-04 Created: 2008-11-04 Last updated: 2017-12-14Bibliographically approved
In thesis
1. Photoswitchable Peptidomimetics: Synthesis and Photomodulation of Functional Peptides
Open this publication in new window or tab >>Photoswitchable Peptidomimetics: Synthesis and Photomodulation of Functional Peptides
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The secondary structure of peptides is of pivotal importance for their biological function. The introduction of photoswitchable moieties into the backbones of peptides provides a unique way of regulating their conformation using an external stimulus, i.e., light. This thesis addresses the design, synthesis, and conformational analysis of photoswitchable peptidomimetics (PSPM). Examples of photomodulation of their functional properties are given.

PSPM were prepared by incorporation of stilbene and thioaurone chromophores (switches) into dipeptides. Synthetic schemes for preparing these chromophores have been developed. Their suitability for incorporation into peptidomimetics has been demonstrated, and the resulting PSPM have been subjected to photoisomerization as well as computational and spectroscopic conformational analysis. The chromophore’s potential as a β-hairpin inducer was particularly interesting.

To investigate the factors that govern the formation of β-hairpins, a series of decapeptides were prepared. Turn regions consisting of amino acids or chromophores were combined with antiparallel peptide strands with hydrophobic side chains. Linear tryptophan zipper peptidomimetics and cyclic peptidomimetics with a second, hairpin-inducing turn region were particularly promising. Comparison between switches revealed that the more flexible stilbene is a better choice for upholding the β-hairpin conformation than the thioaurone.

The catalytic properties of an artificial hydrolase with a helix-loop-helix structure can be improved by introducing a stilbene photoswitch into the loop region. Photoisomerization regulates the catalytic activity of this peptidomimetic, and provides a means to control its aggregation state.

The activity of the enzyme Mycobacterium tuberculosis ribonucleotide reductase was realized by incorporating a stilbene moiety into a linear peptide. Here, one photoisomer proved to be an inhibitor at nM concentrations. A significantly lower effect was observed for the other isomer.

Finally, the decomposition of thioaurones, mainly to thioflavonols and thiaindenes, under conditions used for solid-phase peptide synthesis has been mapped. These findings are expected to have implications for future use of this chromophore.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2008. 70 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 565
Keyword
β-hairpin, peptidomimetics, stilbene, thioaurone, photochemistry
National Category
Organic Chemistry
Identifiers
urn:nbn:se:uu:diva-9345 (URN)978-91-554-7323-5 (ISBN)
Public defence
2008-11-27, B7:101a, BMC, Husargatan 3, Uppsala, 10:15
Opponent
Supervisors
Available from: 2008-11-04 Created: 2008-11-04 Last updated: 2010-12-15Bibliographically approved

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Bergquist, Jonas

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