Abstract:Lektine sind vielversprechende Zielproteine bei der Entdeckung von Wirkstoffen zur Bekämpfung antibiotikaresistenter Keime. Noch sind aber keine nicht‐kohlenhydratbasierten Therapeutika gegen diese Proteinklasse entwickelt worden. Hier präsentieren wir eine Wirkstoff‐zugängliche Bindestelle im β‐Propeller‐Lektin BambL aus Burkholderia ambifaria als mögliches Ziel für allosterische Wirkstoffentwicklung. Diese Bindestelle wurde durch 19F‐NMR‐basiertes Fragmentscreening und einen Computer‐gestützten Algorithmus z… Show more
“…Recent experimental data suggest existence of such druggable secondary sites, especially in mammalian C-type lectins and galectins. [124][125][126][127][128] Examples of allosteric inhibitors include 4-quinolones 129 as DC-SIGN inhibitors (e.g. 19), thiazolopyrimidines (e.g.…”
Section: Other Approachesmentioning
confidence: 99%
“…In contrast, coming from a fragmentbased screening approach, several sub-millimolar inhibitors of BambL have been recently identified. 548 BambL is a lectin of B. ambifaria, causing chronic infections. 501 Evidence from biophysical analysis and single point mutations introduced into the protein suggest an allosteric mode of action.…”
Section: Allosteric Modulation Of Lectinsmentioning
confidence: 99%
“…In this study, 1 H- 15 N HSQC data are presented showing that changes of the chemical environment in secondary sites induced either by weak small molecule binding or by mutation are transferred to remote sites in the protein. 125 Higher affinity ligands are necessary to move these allosteric glycomimetics into further assessment.…”
Section: Allosteric Modulation Of Lectinsmentioning
confidence: 99%
“…Carbohydrate-binding site shown in orange. 125 3.3.2 Galectins. For the galectin family, the development of allosteric glycomimetics initiated not with the existing knowledge on protein flexibility but rather with the discovery of anginex (59, Table 2), a 33-mer cytokine-like artificial peptide binding to Gal-1 with three to four orders higher affinity compared to small carbohydrate ligands.…”
Section: Allosteric Modulation Of Lectinsmentioning
Carbohydrates are essential mediators of many processes in health and disease. The development of glycomimetics as inhibitors and modulators of their lectin receptors has been a success story with numerous molecules reaching clinical stages.
“…Recent experimental data suggest existence of such druggable secondary sites, especially in mammalian C-type lectins and galectins. [124][125][126][127][128] Examples of allosteric inhibitors include 4-quinolones 129 as DC-SIGN inhibitors (e.g. 19), thiazolopyrimidines (e.g.…”
Section: Other Approachesmentioning
confidence: 99%
“…In contrast, coming from a fragmentbased screening approach, several sub-millimolar inhibitors of BambL have been recently identified. 548 BambL is a lectin of B. ambifaria, causing chronic infections. 501 Evidence from biophysical analysis and single point mutations introduced into the protein suggest an allosteric mode of action.…”
Section: Allosteric Modulation Of Lectinsmentioning
confidence: 99%
“…In this study, 1 H- 15 N HSQC data are presented showing that changes of the chemical environment in secondary sites induced either by weak small molecule binding or by mutation are transferred to remote sites in the protein. 125 Higher affinity ligands are necessary to move these allosteric glycomimetics into further assessment.…”
Section: Allosteric Modulation Of Lectinsmentioning
confidence: 99%
“…Carbohydrate-binding site shown in orange. 125 3.3.2 Galectins. For the galectin family, the development of allosteric glycomimetics initiated not with the existing knowledge on protein flexibility but rather with the discovery of anginex (59, Table 2), a 33-mer cytokine-like artificial peptide binding to Gal-1 with three to four orders higher affinity compared to small carbohydrate ligands.…”
Section: Allosteric Modulation Of Lectinsmentioning
Carbohydrates are essential mediators of many processes in health and disease. The development of glycomimetics as inhibitors and modulators of their lectin receptors has been a success story with numerous molecules reaching clinical stages.
“…The use of 19 F-NMR-based experiments in fragment-based screening has been employed also in the search for druggable pockets in multimeric lectins, as in β-propeller lectins. 123 The hits identified by 19 F-NMR were further validated by orthogonal methods, such as SPR and TROSY NMR experiments. In that sense, the NMR approach identified druggable pockets in a bacterial b-propeller lectin, which could be used in the design of allosteric inhibitors.…”
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