Carbohydrate-aromatic interactions mediate many biological processes. However, the structure–energy relationships underpinning direct carbohydrate–aromatic packing in aqueous solution have been difficult to assess experimentally and remain elusive. Here, we determine the structures and folding energetics of chemically synthesized glycoproteins to quantify the contributions of the hydrophobic effect and CH–π interactions to carbohydrate–aromatic packing interactions in proteins. We find that the hydrophobic effect contributes significantly to protein–carbohydrate interactions. Interactions between carbohydrates and aromatic amino acid side chains, however, are supplemented by CH–π interactions. The strengths of experimentally determined carbohydrate–π interactions do not correlate with the electrostatic properties of the involved aromatic residues, suggesting that the electrostatic component of CH–π interactions in aqueous solution is small. Thus, tight binding of carbohydrates and aromatic residues is driven by the hydrophobic effect and CH–π interactions featuring a dominating dispersive component.
We herein describe the first synthesis of iminosugar C-glycosides of α-d-GlcNAc-1-phosphate in 10 steps starting from unprotected d-GlcNAc. A diastereoselective intramolecular iodoamination–cyclization as the key step was employed to construct the central piperidine ring of the iminosugar and the C-glycosidic structure of α-d-GlcNAc. Finally, the iminosugar phosphonate and its elongated phosphate analogue were accessed. These phosphorus-containing iminosugars were coupled efficiently with lipophilic monophosphates to give lipid-linked pyrophosphate derivatives, which are lipid II mimetics endowed with potent inhibitory properties toward bacterial transglycosylases (TGase).
Nature has developed complex enzymatic machineries that promote the macrocyclization of linear precursors and provide a multitude of macrocyclic natural polyketides, peptides, and depsipeptides. [1,2] Macrocyclization of a ligand generally scales its receptor affinity and selectivity. [3][4][5] The large number of biologically active macrocyclic agents found in nature has prompted chemists to develop synthetic macrocyclization strategies for a large number of valuable protein ligands. [6,7] Synthetic cyclic peptides like the anti-cancer agents octreotide [8] and cilengitide [9] are success stories of drug design, and their potencies are ascribed to their bioactive conformations.[10]The modular composition of peptides facilitates the systematic variation of side chains, chirality and backbone chain length, and expedites the analysis of how these parameters affect biological activity. As determinants of the three-dimensional structure, these factors should also influence the inclination of a linear precursor to form a ring-closed structure. However, the thermodynamics of the ring-chain equilibrium of complex biomolecules has so far resisted quantitative experimental analysis, and therefore medicinal chemistry relies on computer modeling.[11] Through the establishment of the temperature dependent ring-chain equilibria of imino peptides, we were able to experimentally characterise the macrocyclization of a biomolecule and quantify the involved reaction entropy. Although obtained for a single ring size, these results are instructive for macrocyclization in general.Biosynthetic macrocyclizations, like cyclopeptide formation, are generally irreversible in aqueous solution-a feature which adds to the stability of the macrocycle but prevents formation of the ring-chain equilibrium necessary for thermodynamic analysis (Figure 1 A). In this context, the nostocyclopeptides A1 (ncpA1) and A2 (ncpA2) turned out to be suitable candidates for the investigation of the macrocyclization process (Figure 1 C). These cyclic heptapeptides stand out by a hitherto unique backbone imino linkage, which is formed between a Cterminal aldehyde hydrate and an N-terminal amine (Figure 1 B). [12][13][14] The reversibility of imine formation in aqueous solution [15,16] should, under appropriate conditions, allow for the thermodynamic analysis of the equilibria between the linear and the cyclic peptides.Nostocyclopeptides have all the prerequisites necessary for the quantitative examination of a ring-chain equilibrium, including great selectivity for head-to-tail intramolecular cyclization and reluctance to form dimers or other linear or cyclic oligomerization byproducts. This is remarkable, as intermolecular oligomerization always competes with intramolecular ring closure [17,18] and normally occurs for macrocyclic imines, like the numerous examples studied in the field of supramolecular chemistry. [19] In contrast, the nostocyclopeptides, though highly decorated with stereocenters and functional groups, exhibit simple ring-chain equilibria that ...
In spite of the important role of peptide macrocyclizations for the generation of conformationally constrained biological ligands, our knowledge of factors that determine the inclination of a substrate to cyclize is low. Therefore, methods that give access to the thermodynamic characterization of these processes are desirable. In this work, we present the isosteric substitution of the amide ligation site of a cyclopeptide by an imine. Applied to the decapeptide antibiotic Tyrocidine A (TycA), the reversible cyclization of the linear aldehyde TycA-CHO resulted in the unexpectedly stable hemiaminal Psi[CH(OH)NH]-TycA, which is equivalent to the tetrahedral intermediate of macrolactamization, and which is observed for the first time in a peptidic structure. On the basis of NMR spectroscopy and molecular modeling, we discuss the observed high stereoselectivity of hemiaminal formation, as well as its reluctance to be dehydrated to the imine. As required for thermodynamic analysis, it is possible to establish a pH- and temperature-dependent cyclization equilibrium, which allows determination of the entropy loss of the peptide chain, and quantification of the extent of preorientation of the cyclization precursor.
Whereas the C-terminal fragment of neuropeptide Y (NPY) has been structurally well-defined both in solution and as membrane-bound, detailed structural information regarding the proline-rich N-terminus is still missing. The systematic variation of each position by a conformationally constrained pyridone dipeptide building block within the amino terminal segment of NPY leads to a systematic receptor subtype selectivity of the neuropeptide. Thereby, the systematic dipeptide scan proved superior to the traditional L-Ala scan because it showed how to modify the N-terminus in order to obtain increasingly more Y1 or Y5 receptor selective ligands. NMR and CD spectroscopic analyses were used to characterize the stepwise rigidification of the N-terminus of NPY when up to three dipeptide building blocks were incorporated by solid-phase peptide synthesis. The pyridone dipeptide increases the hydrophobicity of the amino terminus of NPY, and this allows the tuning of the membrane affinity of NPY. The amphiphilic C-terminal helix of 3-fold-substituted NPY thus becomes visible by selective line broadening in the (1)H NMR. Accordingly, we could structurally characterize protein segments that are too flexible for other methods.
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