uu.seUppsala University Publications
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Phototriggerable peptidomimetics for the inhibition of Mycobacterium turberculosis ribonucleotide reductase by targeting protein-protein binding
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC.
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Synthetical Organic Chemistry.
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Synthetical Organic Chemistry.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
Show others and affiliations
2015 (English)In: Organic and biomolecular chemistry, ISSN 1477-0520, E-ISSN 1477-0539, Vol. 13, no 9, 2612-2621 p.Article in journal (Refereed) 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.

Place, publisher, year, edition, pages
2015. Vol. 13, no 9, 2612-2621 p.
National Category
Organic Chemistry Medicinal Chemistry
Research subject
Chemistry with specialization in Organic Chemistry; Medicinal Chemistry
Identifiers
URN: urn:nbn:se:uu:diva-239491DOI: 10.1039/C4OB01926AISI: 000350144600018PubMedID: 25580895OAI: oai:DiVA.org:uu-239491DiVA: diva2:774700
Funder
Swedish Research Council
Available from: 2014-12-28 Created: 2014-12-28 Last updated: 2017-12-05Bibliographically approved
In thesis
1. Light-Triggered Conformational Switches for Modulation of Molecular Recognition: Applications for Peptidomimetics and Supramolecular Systems
Open this publication in new window or tab >>Light-Triggered Conformational Switches for Modulation of Molecular Recognition: Applications for Peptidomimetics and Supramolecular Systems
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
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).

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2015. 61 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 1329
Keyword
Bisporphyrin tweezers, peptidomimetics, host-guest systems, conformational analysis, supramolecular chemistry, photochemistry
National Category
Chemical Sciences
Research subject
Organic Chemistry; Chemistry with specialization in Organic Chemistry
Identifiers
urn:nbn:se:uu:diva-267845 (URN)978-91-554-9431-5 (ISBN)
Public defence
2016-01-28, B41, BMC, Husargatan 3, Uppsala, 10:15 (English)
Opponent
Supervisors
Available from: 2016-01-04 Created: 2015-11-27 Last updated: 2016-01-13Bibliographically approved

Open Access in DiVA

No full text

Other links

Publisher's full textPubMed

Authority records BETA

Karlsson, ChristofferBlom, MagnusKarlén, AndersGogoll, Adolf

Search in DiVA

By author/editor
Karlsson, ChristofferBlom, MagnusKarlén, AndersGogoll, Adolf
By organisation
Department of Chemistry - BMCSynthetical Organic ChemistryDepartment of Cell and Molecular BiologyOrganic Pharmaceutical Chemistry
In the same journal
Organic and biomolecular chemistry
Organic ChemistryMedicinal Chemistry

Search outside of DiVA

GoogleGoogle Scholar

doi
pubmed
urn-nbn

Altmetric score

doi
pubmed
urn-nbn
Total: 1560 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf