Photoswitchable Peptidomimetics: Synthesis and Photomodulation of Functional Peptides

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…


1 Aims of the Present Study
2 Introduction
2.1 General Introduction
2.2 Peptide Secondary-Structure Motifs: β-Hairpins
2.3 β-Hairpin Mimetics
2.4 Light-Triggered Alteration of Chemical Structures
2.4.1 Photomodulable Biological Systems
2.4.2 Photoisomerizations
2.4.3 Artificial Photomodulators: Switches
2.4.4 Photoswitchable Peptidomimetics: What is Known?
3 Overview of Experimental and Theoretical Methods
3.1 Solid-Phase Peptide Synthesis (SPPS)
3.2 Conformational Analysis
3.2.1 X-Ray Diffraction
3.2.2 Circular Dichroism Spectroscopy
3.2.3 Nuclear Magnetic Resonance Spectroscopy
3.2.4 Computational Methods
4 Results and Discussion
4.1 Synthesis and Conformational Analysis of Novel Photoswitchable Peptidomimetics (Paper I)
4.1.1 Synthesis
4.1.2 Conformational Analysis
4.1.3 Conclusions and Outlook
4.2 Hairpin-Stabilizing Factors in Combination with Photoswitchable Turn Moieties (Paper II)
4.2.1 Design and Synthesis of Peptides and Peptidomimetics
4.2.2 Conformational Analysis by NMR Spectroscopy
4.2.3 Conformational Analysis by CD Spectroscopy
4.2.4 Conclusions and Outlook
4.3 Controlling the Physiological Activity of Peptides by Photoisomerization (Papers III and IV)
4.3.1 A Designed Photoswitchable Polypeptide Catalyst (Paper III)
4.3.2 Photoswitchable Peptidomimetics for the Inhibition of
Mycobacterium tuberculosis Ribonucleotide Reductase (Paper IV)
4.4 Decomposition of Thioaurones During SPPS (Paper V)
4.4.1 Deciphering the Thioaurone Decomposition
4.4.2 Conclusions
5. Concluding Remarks
6. Summary in Swedish

Author: Varedian, Miranda

Source: Uppsala University Library

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