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Phototriggerable peptidomimetics for the inhibition of Mycobacterium turberculosis ribonucleotide reductase by targeting protein-protein binding
Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC.
Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Syntetisk organisk kemi.
Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Syntetisk organisk kemi.
Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi.
Vise andre og tillknytning
2015 (engelsk)Inngår i: Organic and biomolecular chemistry, ISSN 1477-0520, E-ISSN 1477-0539, Vol. 13, nr 9, s. 2612-2621Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Incorporation of an artificial amino acid 2 with a stilbene chromophore into peptidomimetics with three to nine amino acids yields phototriggerable candidates for inhibition of the binding between the R1 and R2 subunits of the M. tuberculosis ribonucleotide reductase (RNR). Interstrand hydrogen bond probability was used as a guideline for predicting conformational preferences of the photoisomers. Binding of these inhibitors has been rationalized by docking studies with the R1 unit. Significant differences in binding of the photoisomers were observed. For the shorter peptidomimetics, stronger binding of the Z isomer might indicate hydrophobic interactions between the stilbene chromophore and the binding site.

sted, utgiver, år, opplag, sider
2015. Vol. 13, nr 9, s. 2612-2621
HSV kategori
Forskningsprogram
Kemi med inriktning mot organisk kemi; Läkemedelskemi
Identifikatorer
URN: urn:nbn:se:uu:diva-239491DOI: 10.1039/C4OB01926AISI: 000350144600018PubMedID: 25580895OAI: oai:DiVA.org:uu-239491DiVA, id: diva2:774700
Forskningsfinansiär
Swedish Research CouncilTilgjengelig fra: 2014-12-28 Laget: 2014-12-28 Sist oppdatert: 2018-01-11bibliografisk kontrollert
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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