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Photoswitchable peptidomimetics with a stiff-stilbene chromophore for inhibition of Mycobacterium tuberculosis RNR
Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Syntetisk organisk kemi.
Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Tekniska sektionen, Institutionen för teknikvetenskaper, Nanoteknologi och funktionella material.
Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för biokemi och organisk kemi, Organisk kemi I.
(engelsk)Manuskript (preprint) (Annet vitenskapelig)
Abstract [en]

Peptidomimetics incorporating two amino acids 1 and 2 with a stiff stilbene chromophore have been screened by a computational study and compared to a previously investigated analog 3 with stilbene chromophore. The effect of E-Z isomerization of the chromophores on the conformational properties of the petidomimetics was assessed via the frequency of hydrogen bonding between the two peptide strands attached to either side of the chromophore. Substantial differences between the three amino acids were thus indicated, in line with the anticipated effect of chromophore rigidity variation.

Emneord [en]
Peptidomimetics, conformational analysis
HSV kategori
Forskningsprogram
Kemi med inriktning mot organisk kemi
Identifikatorer
URN: urn:nbn:se:uu:diva-267830OAI: oai:DiVA.org:uu-267830DiVA, id: diva2:874521
Forskningsfinansiär
Swedish Research Council, 621-2012-3379Tilgjengelig fra: 2015-11-27 Laget: 2015-11-27 Sist oppdatert: 2016-01-13
Inngår i avhandling
1. Light-Triggered Conformational Switches for Modulation of Molecular Recognition: Applications for Peptidomimetics and Supramolecular Systems
Åpne denne publikasjonen i ny fane eller vindu >>Light-Triggered Conformational Switches for Modulation of Molecular Recognition: Applications for Peptidomimetics and Supramolecular Systems
2015 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
Abstract [en]

The main focus of this thesis is on photochemical modulation of molecular recognition in various host-guest systems. This involves the design, synthesis and integration of light-triggered conformational switches into peptidomimetic guests and molecular tweezer hosts. The impact of the switches on guest and host structures has been assessed by spectroscopic and computational conformational analysis. Effects of photochemical structure modulation on molecular recognition in protein-ligand and supramolecular host-guest systems are discussed.

Phototriggerable peptidomimetic inhibitors of the enzyme M. tuberculosis ribonucleotide reductase (RNR) were obtained by incorporation of a stilbene based amino acid moiety into oligopeptides between 3-9 residues long (Paper I). Interstrand hydrogen bond probability in the E and Z forms of the peptidomimetics was used as a tool for predicting conformational preferences. Considerable differences in inhibitory potency for the E and Z photoisomers were demonstrated in a binding assay.

In order to advance the concept of photomodulable inhibitors, synthetic routes towards amino acid derivatives based on the more rigid stiff-stilbene chromophore were developed (Paper II).  The effect of E-Z isomerization on the conformational properties of peptidomimetic inhibitors incorporating the stiff-stilbene chromophore was also assessed computationally (Paper III). It was indicated that inhibitors with the more rigid amino acid derivative should display larger conformational divergence between photoisomers than corresponding stilbene derivatives.

Bisporphyrin tweezers with enediyne and stiff-stilbene spacers have been synthesized, and the conformational characteristics imposed by the spacers have been studied and compared to a glycoluril linked tweezer. The effects of spacers on tweezer binding of diamine guests and helicity induction by chiral guests have been investigated (Paper IV). Connections between spacer flexibility and host-guest binding strength have been established. The structural properties of the stiff-stilbene spaced tweezer made it particularly susceptible to helicity induction by both monotopic and bitopic chiral guests. Finally, the possibility of photochemical bite-size variation of tweezers with photoswitchable spacers has been assessed. Initial studies have shown that photoisomerization of the tweezers is possible without photochemical decomposition. Conformational analyses indicate that isomerization should impact binding characteristics of the tweezers to a significant extent (Paper V).

sted, utgiver, år, opplag, sider
Uppsala: Acta Universitatis Upsaliensis, 2015. s. 61
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 1329
Emneord
Bisporphyrin tweezers, peptidomimetics, host-guest systems, conformational analysis, supramolecular chemistry, photochemistry
HSV kategori
Forskningsprogram
Organisk kemi; Kemi med inriktning mot organisk kemi
Identifikatorer
urn:nbn:se:uu:diva-267845 (URN)978-91-554-9431-5 (ISBN)
Disputas
2016-01-28, B41, BMC, Husargatan 3, Uppsala, 10:15 (engelsk)
Opponent
Veileder
Tilgjengelig fra: 2016-01-04 Laget: 2015-11-27 Sist oppdatert: 2016-01-13bibliografisk kontrollert

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