Abstract
Peptide based lectin mimetics represent an attractive approach for the development of artificial carbohydrate receptors that might find application in bio-analytical and medicinal fields. Taking into consideration the structure of typical lectin binding site, we have designed a novel artificial receptor molecule possessing a rigid three-dimensional structure, hydrogen-bonding site and lipophilic binding pocket to promote hydrophobic interaction and hydrogen-bonding. A new solid- phase synthetic approach that allows complete synthesis of desired bicyclic peptide 1 on the solid support was developed. CD spectra of peptides 1 and 2 indicate that the structure of 1 is rather rigid and preorganised for the three-dimensional monosaccharide substrates binding. The binding affinities of bicyclic peptide receptor 1 toward various carbohydrate substrates at physiologically relevant conditions were estimated by UV/vis and fluorimetric titration experiments, and the observed values are in the millimolar range. With these results we have demonstrated that the bicyclic peptide 1 represent a promising basis for the design of new and more efficient carbohydrate receptors that may have broader application in bio-analytical or medicinal field.
Highlights
C ARBOHYDRATE recognition is one of the most sophisticated recognition processes in biological systems.[1]
Binding was achieved through a combination of hydrogen bonding to the monosaccharide hydroxyl groups and van der Waals packing of the hydrophobic sugar face against aromatic amino acid side chains forming sandwich-type interactions.[4b,4d] Taking into consideration these binding principles, a variety of receptors for monosaccharide binding in organic solvent have been prepared.[2a,3a] construction of artificial receptors for binding of carbohydrates in water represent challenging task, mainly due to the weak hydrogen-bonding interactions
The conformationally constrained cage-like molecules, such as bicyclic peptide receptor 1, represent an interesting topology for designing artificial receptors capable of binding biologically important monosaccharides under physiological conditions
Summary
C ARBOHYDRATE recognition is one of the most sophisticated recognition processes in biological systems.[1]. Considering the importance of the carbohydrate recognition, it is not surprising that design and synthesis of artificial receptors for these important biological substrates attracted a great deal of attention in biomimetic chemistry.[2] Current efforts are mainly focused on the design of receptors for complexation of mono- or disaccharides.[2a,3] This crude simplification has been based on the structural studies of the lectins, revealing that carbohydrate binding sites are typically shallow binding pockets where only binding of the terminal monosaccharide moieties can occur.[4] Binding of an individual lectin to monosaccharide substrate is extremely weak; the association constant (Ka) for these complexes are typically in the 10–4 – 10–2 mol–1dm range. Binding was achieved through a combination of hydrogen bonding to the monosaccharide hydroxyl groups and van der Waals packing of the hydrophobic sugar face against aromatic amino acid side chains forming sandwich-type interactions.[4b,4d] Taking into consideration these binding principles, a variety of receptors for monosaccharide binding in organic solvent have been prepared.[2a,3a] construction of artificial receptors for binding of carbohydrates in water represent challenging task, mainly due to the weak hydrogen-bonding interactions
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