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SEAL by NMR: Glyco-Based Selenium-Labeled Affinity Ligands Detected by NMR Spectroscopy
Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
2014 (engelsk)Inngår i: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 20, nr 43, s. 13905-13908Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

We report a method for the screening of interactions between proteins and selenium-labeled carbohydrate ligands. SEAL by NMR is demonstrated with selenoglycosides binding to lectins where the selenium nucleus serves as an NMR-active handle and reports on binding through Se-77 NMR spectroscopy. In terms of overall sensitivity, this nucleus is comparable to C-13 NMR, while the NMR spectral width is ten times larger, yielding little overlap in Se-77 NMR spectroscopy, even for similar compounds. The studied ligands are singly selenated bioisosteres of methyl glycosides for which straightforward preparation methods are at hand and libraries can readily be generated. The strength of the approach lies in its simplicity, sensitivity to binding events, the tolerance to additives and the possibility of having several ligands in the assay. This study extends the increasing potential of selenium in structure biology and medicinal chemistry. We anticipate that SEAL by NMR will be a beneficial tool for the development of selenium-based bioactive compounds, such as glycomimetic drug candidates.

sted, utgiver, år, opplag, sider
2014. Vol. 20, nr 43, s. 13905-13908
Emneord [en]
Se-77 NMR spectroscopy, lectins, protein-ligand interactions, SEAL, selenoglycosides
HSV kategori
Forskningsprogram
organisk kemi
Identifikatorer
URN: urn:nbn:se:su:diva-109971DOI: 10.1002/chem.201404933ISI: 000343800700012OAI: oai:DiVA.org:su-109971DiVA, id: diva2:768717
Forskningsfinansiär
Swedish Research CouncilKnut and Alice Wallenberg Foundation
Merknad

AuthorCount:3;

Tilgjengelig fra: 2014-12-04 Laget: 2014-12-02 Sist oppdatert: 2017-12-05bibliografisk kontrollert
Inngår i avhandling
1. The sweet side of molecular structure: NMR spectroscopic studies of glycans and their interactions with proteins
Åpne denne publikasjonen i ny fane eller vindu >>The sweet side of molecular structure: NMR spectroscopic studies of glycans and their interactions with proteins
2015 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
Abstract [en]

In this thesis, within the topic of bioorganic chemistry, the molecular structure of carbohydrates has been studied. Carbohydrates, or glycans, are ubiquitous biomolecules exhibiting a wide range of biological roles. The specific functions of these molecules are largely determined by their interactions with proteins and molecular structure ultimately governs such specialized recognition events.

Glycan-binding proteins, such as lectins or enzymes, often interact with their sweet ligands in a transient fashion and nuclear magnetic resonance spectroscopy (NMR) is a viable technique to probe these complexes. In particular, ligand-based NMR techniques have been employed, typically in combination with other biophysical as well as biochemical and computational methods. The aim of this work has been to gain new insights about specific biological systems, to develop methods and to devise protocols for their studies.

The first two papers cover NMR-interaction studies of native ligands as well as inhibitor glycans with the enzyme hen egg-white lysozyme and the lectin botulinum neurotoxin type A. Screening experiments were performed to investigate ligand affinities and selectivities. Solution models in combination with X-ray crystal structures were compared in order to evaluate their agreement and the details of interactions.

A method for application in carbohydrate ligand NMR-screening was developed in paper three. The heteronucleus selenium was exploited as a reporter of selenoglycosides binding to lectins. 77Se NMR spectroscopy proved sensitive to binding events and the presented approach should be useful in large screenings of glycomimetic inhibitors.  In order to obtain sufficient amounts of glycans for bioorganic studies their production often relies on chemical synthesis. In the last paper, the structure of some conformationally highly activated glycosyl donors was thoroughly investigated and related to their reactivity in synthetic glycosylation reactions.  

sted, utgiver, år, opplag, sider
Stockholm: Department of Organic Chemistry, Stockholm University, 2015. s. 77
Emneord
bioorganic chemistry, glycans, ligand-based NMR, molecular simulations, protein-carbohydrate interactions, lectins, carbohydrate conformations, 77Se NMR, structure-reactivity relationships, super-armed donors
HSV kategori
Forskningsprogram
organisk kemi
Identifikatorer
urn:nbn:se:su:diva-112350 (URN)978-91-7649-083-9 (ISBN)
Disputas
2015-02-20, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 16 B, Stockholm, 10:00 (engelsk)
Opponent
Veileder
Merknad

At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 3: Manuscript. Paper 4: Manuscript.

 

Tilgjengelig fra: 2015-01-29 Laget: 2015-01-12 Sist oppdatert: 2017-10-11bibliografisk kontrollert

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