Glycopeptide Mimetics Research Articles

Glycopeptides and -Mimetics to Detect, Monitor and Inhibit Bacterial and Viral Infections: Recent Advances and Perspectives.

The initial contact of pathogens with host cells is usually mediated by their adhesion to glycan structures present on the cell surface in order to enable infection. Furthermore, glycans play important roles in the modulation of the host immune responses to infection. Understanding the carbohydrate-pathogen interactions are of importance for the development of novel and efficient strategies to either prevent, or interfere with pathogenic infection. Synthetic glycopeptides and mimetics thereof are capable of imitating the multivalent display of carbohydrates at the cell surface, which have become an important objective of research over the last decade. Glycopeptide based constructs may function as vaccines or anti-adhesive agents that interfere with the ability of pathogens to adhere to the host cell glycans and thus possess the potential to improve or replace treatments that suffer from resistance. Additionally, synthetic glycopeptides are used as tools for epitope mapping of antibodies directed against structures present on various pathogens and have become important to improve serodiagnostic methods and to develop novel epitope-based vaccines. This review will provide an overview of the most recent advances in the synthesis and application of glycopeptides and glycopeptide mimetics exhibiting a peptide-like backbone in glycobiology.

Sequence isomerism-dependent self-assembly of glycopeptide mimetics with switchable antibiofilm properties.

In biological systems, diverse amino acid sequences and functional decorations endow proteins with specific functions. Functionally modified oligopeptides are attractive building blocks to assemble stimuli-responsive biomimetic superstructures for mimicking soft structures in nature and biomaterial applications. In this work, we selectively synthesized the structurally simplest isomeric tripeptides (i.e., Ala-Gly-Gly-OH, Gly-Ala-Gly-OH and Gly-Gly-Ala-OH) to demonstrate how the subtlest change in sequence isomerism influences the self-assembly of glycopeptides. To impart self-assembly capability and stimuli-responsiveness, the isomeric tripeptides were modified with a hydrophobic n-butylazobenzene tail at the N-terminal. We observed three different self-assembled 1-D morphologies (i.e., nanotwists, nanoribbons and nanofibers) from the azobenzene-glycopeptides (AGPs) under the same conditions when the position of the Ala residue was switched. Experimental methods including transmission electron microscopy (TEM), atomic force microscopy (AFM), X-ray diffraction (XRD), Fourier transform infrared (FT-IR) spectroscopy and circular dichroism (CD) spectroscopy were used to characterize the structural details of glycopeptide mimetic assemblies. Martini coarse-grained molecular dynamics (MD) simulations confirmed such structural observations and investigated the differences in assembly mechanisms. Furthermore, the glycopeptide mimetic assemblies showed a reversible disassembly-assembly process in response to temperature, light or host-guest chemistry, and can be used as switchable antibiofilm nanoagents.

ChemInform Abstract: The Long Underestimated Carbonyl Function of Carbohydrates — An Organocatalyzed Shot into Carbohydrate Chemistry

AbstractReview: [38 refs.

The long underestimated carbonyl function of carbohydrates – an organocatalyzed shot into carbohydrate chemistry.

The aggressive and strong development of organocatalysis provides several protocols for the convenient utilization of the carbonyl function of unprotected carbohydrates in C-C-bond formation processes. These amine-catalyzed mechanisms enable multiple cascade-protocols for the synthesis of a wide range of carbohydrate-derived compound classes. Several, only slightly different protocols, have been developed for the application of 1,3-dicarbonyl compounds in the stereoselective chain-elongation of unprotected carbohydrates and the synthesis of highly functionalized C-glycosides of defined configuration. In addition, C-glycosides can also be accessed by amine-catalyzed reactions with methyl ketones. By a one-pot cascade reaction of isocyanides with unprotected aldoses and amino acids access to defined configured glycopeptide mimetics is achieved. Depending on the reaction conditions different origins to control the installation of configuration during the bond-formation process were observed.

Solid‐Phase Synthesis of Phosphoramidate‐Linked Glycopeptides

AbstractThe synthesis of stable glycopeptide mimetics is of particular interest in bioorganic chemistry to allow access of glycoconjugates for biological investigations. In this paper, a straightforward solid‐phase synthesis of a novel glycopeptide mimetic by a Staudinger phosphite reaction is presented. Thereby, a dimethyl phosphite containing peptide, which is obtained by standard phosphitylation of a Ser residue, is treated on the solid support with glycosyl azides, delivering phosphoramidate‐linked glycoconjugates. These artificial glycopeptides show excellent stability under acidic and physiological conditions.

α‐O‐Linked Glycopeptide Mimetics: Synthesis, Conformation Analysis, and Interactions with Viscumin, a Galactoside‐Binding Model Lectin

Efficient cycloaddition of a silylidene-protected galactal with a suitable heterodiene yielded the basis for a facile diastereoselective route to a glycopeptide-mimetic scaffold. Its carbohydrate part was further extended by beta1-3-linked galactosylation. The pyranose rings retain their (4)C(1) chair conformation, as shown by molecular modeling and NMR spectroscopy, and the typical exo-anomeric geometry was observed for the disaccharide. The expected bioactivity was ascertained by saturation-transfer-difference NMR spectroscopy by using the galactoside-specific plant toxin viscumin as a model lectin. The experimental part was complemented by molecular docking. The described synthetic route and the strategic combination of computational and experimental techniques to reveal conformational properties and bioactivity establish the prepared alpha-O-linked glycopeptide mimetics as promising candidates for further exploitation of this scaffold to give O-glycans for lectin blocking and vaccination.

A New Scaffold for the Stereoselective Synthesis of α‐O‐Linked Glycopeptide Mimetics.

AbstractFor Abstract see ChemInform Abstract in Full Text.

A new scaffold for the stereoselective synthesis of alpha-O-linked glycopeptide mimetics.

alpha-O-Linked glycohomoglutamates are obtained as diastereomerically pure compounds by chemo-, regio-, and stereoselective cycloadditions between glycals and aspartic acid derivatives. The latter constitute orthogonally functionalized scaffolds for glycopeptide mimetics.

Cyanogen bromide cleavage generates fragments suitable for expressed protein and glycoprotein ligation.

Herein cyanogen bromide is employed for the efficient production of N-terminal cysteine containing protein fragments for expressed protein ligation (EPL) from polyhistidine-tagged precursors. We provide three examples of efficient CNBr cleavage of fragments of the glycoprotein erythropoietin that can be ligated with peptides or glycopeptide mimetics potentially giving rise to semisynthetic glycoprotein therapeutics.

Glucuronic acid derivatives as branching units for the synthesis of glycopeptide mimetics.

Natural glycopeptides and glycoproteins exhibit a large structural diversity, which can be mimicked by synthetic glycopeptide derivatives to assist the investigation of biological functions and structure-activity relationships. Here, dendronized saccharides were synthesized to provide glycosyl amino acids, equipped with a branching element for the preparation of branched glycopeptide mimetics. An optimized Staudinger-type reaction served as key reaction en route to the complex glycopeptide 14, in which three mannose moieties were connected to the branched glucuronyl scaffold.

Asparagine surrogates for the assembly of N-linked glycopeptide mimetics by chemoselective ligation

Abstract Alanine-β-hydroxylamine (Aβx) and alanine-β-hydrazide (Aβz) have been developed as asparagine surrogates for the assembly of N -linked glycopeptide mimetics by chemoselective ligation. The utility of these residues is illustrated with the synthesis of the oligosaccharyl transferase substrate mimetics 1 and 2 , and conjugation thereof with GlcNAc to obtain the N -glycopeptide mimetics 3 and 4 .

Chemoselective elaboration of O-linked glycopeptide mimetics by alkylation of 3-thioGalNAc.

A critical branch point in mucin-type oligosaccharides is the beta 1-->3 glycosidic linkage to the core alpha-N-acetylgalactosamine (GalNAc) residue. We report here a strategy for the synthesis of O-linked glycopeptide analogues that replaces this linkage with a thioether amenable to construction by chemoselective ligation. The key building block was a 2-azido-3-thiogalactose-Thr analogue that was incorporated into a peptide by fluorenylmethoxycarbonyl (Fmoc)-based solid-phase peptide synthesis. Higher order oligosaccharides were readily generated by alkylation of the corresponding 3-thioGalNAc with N-bromoacetamido sugars. The rapid assembly of "core 1"and "core 3" O-linked glycopeptide mimetics was accomplished in this fashion.

New Directions in the Synthesis of Glycopeptide Mimetics

Structural and functional mimetics of naturally occurring glycopeptides are attractive synthetic targets owing to their potential as biological tools and therapeutic agents. The syntheses of C- and S-glycopeptides, glycopeptoids, and oxime- (figure) and thioether-linked glycopeptides have now been realized, and many of these mimetics are currently undergoing biological evaluation.

New Directions in the Synthesis of Glycopeptide Mimetics

Structural and functional mimetics of naturally occurring glycopeptides are attractive synthetic targets owing to their potential as biological tools and therapeutic agents. The syntheses of C- and S-glycopeptides, glycopeptoids, and oxime- (figure) and thioether-linked glycopeptides have now been realized, and many of these mimetics are currently undergoing biological evaluation.