Synthesis of -glycoside analogues of isopropyl β-D-1-thiogalactopyranoside (IPTG) and 1-β-D-galactopyranosyl-2-methylpropane. Conformational analysis and evaluation as inhibitors of the lac repressor in and as galactosidase inhibitors.

Isopropyl 1-thio-β-D-galactopyranoside (IPTG, 1) is used widely as an inducer of protein expression in and 1-β-D-galactopyranosyl-2-methylpropane (2), a -glycoside analogue of 1, has also been identified as an inducer. Here, synthesis and study of mimetics of 1 and 2, 1-β-D-galactopyranosyl-2-methylpropan-1-ols and two cyclic acetals derivatives, that constrain the presentation of the iPr group in various geometries is described. Conformational analysis of -glycosides in protic solvent is performed using (i) Desmond metadynamics simulations (OPLS4) and (ii) use of values obtained by H-NMR spectroscopy.

Small lectin ligands as a basis for applications in glycoscience and glycomedicine.

Glycan recognition by lectins mediates important biological events. This Tutorial Review aims to introduce lectin-ligand interactions and show how these molecular recognition events inspire innovations such as: (i) glycomimetic ligands; (ii) multivalent ligand agonists/antagonists; (iii) ligands for precision delivery of therapies to cells, where therapies include vaccines, siRNA and LYTACs (iv) development of diagnostics. A small number of case studies are selected to demonstrate principles for development of new ligands for applications inspired by knowledge of natural glycan ligand structure and function.

Flow Chemistry for Synthesis of 2-(C-Glycosyl)acetates from Pyranoses via Tandem Wittig and Michael Reactions.

C-Glycosyl compounds (C-glycosides) are a class of saccharide derivatives with improved stability over their O-linked counterparts. This paper reports the synthesis of several -2-(C-glycosyl)acetates via a tandem Wittig-Michael reaction from pyranoses (cyclic hemiacetals) using continuous flow processing, which gave improvements compared to reactions conducted in round-bottom flasks. Products were isolated in yields of >60% from reactions of benzyl-protected xylopyranoses, glucopyranoses, and galactopyranoses at higher temperatures and pressures, which were superior to yields from batch procedures.

Application of Sublimation in the Synthesis and Crystal Growth of Organosulfones.

The solvent-free elimination of sulfinic acid and aromatization of 1,6-trans-substituted bis(arylsulfone) trienes is reported. It is shown that sublimation can be used as a 'green' method to combine the thermal transformation of six trienes and the crystal growth of the resulting 4-(phenylsulfonyl)biphenyls. When the sublimation conditions are carefully controlled, high quality single crystals of the 4-(phenylsulfonyl)biphenyls are obtained.

MUC1 Glycopeptide Vaccine Modified with a GalNAc Glycocluster Targets the Macrophage Galactose C-type Lectin on Dendritic Cells to Elicit an Improved Humoral Response.

Mucin expression and glycosylation patterns on cancer cells differ markedly from healthy cells. Mucin 1 (MUC1) is overexpressed in several solid tumors and presents high levels of aberrant, truncated O-glycans (e.g.

Flow chemistry based catalytic hydrogenation for improving the synthesis of 1-deoxynojirimycin (DNJ) from an l-sorbose derived precursor.

1-Deoxynojirimycin (1-DNJ) is a glycoprocessing inhibitor, and it serves as a synthetic precursor to two of three currently marketed iminosugar drugs, miglustat (N-butyl DNJ/Zavesca®) and miglitol (Glyset®). Herein a continuous flow procedure is presented that shortens a synthesis of 1-DNJ from an intermediate prepared from l-sorbose. Batch reactions involving an azide reduction, subsequent reductive amination-based cyclisation, and O-benzyl deprotection in a previous report required two steps and the use of an acid.

Targeting osteoarthritis-associated galectins and an induced effector class by a ditopic bifunctional reagent: Impact of its glycan part on binding measured in the tissue context.

Pairing glycans with tissue lectins controls multiple effector pathways in (patho)physiology. A clinically relevant example is the prodegradative activity of galectins-1 and -3 (Gal-1 and -3) in the progression of osteoarthritis (OA) via matrix metalloproteinases (MMPs), especially MMP-13. The design of heterobifunctional inhibitors that can block galectin binding and MMPs both directly and by preventing their galectin-dependent induction selectively offers a perspective to dissect the roles of lectins and proteolytic enzymes.

A cell free biomembrane platform for multimodal study of influenza virus hemagglutinin and for evaluation of entry-inhibitors against hemagglutinin.

Seasonal periodic pandemics and epidemics caused by Influenza A viruses (IAVs) are associated with high morbidity and mortality worldwide. They are frequent and unpredictable in severity so there is a need for biophysical platforms that can be used to provide both mechanistic insights into influenza virulence and its potential treatment by anti-IAV agents. Host membrane viral association through the glycoprotein hemagglutinin (HA) of IAVs is one of the primary steps in infection.

Protecting group principles suited to late stage functionalization and global deprotection in oligosaccharide synthesis.

Chemical synthesis is a powerful tool to access homogeneous complex glycans, which relies on protecting group (PG) chemistry. However, the overall efficiency of chemical glycan assembly is still low when compared to oligonucleotide or oligopeptide synthesis. There have been many contributions giving rise to collective improvement in carbohydrate synthesis that includes PG manipulation and stereoselective glycoside formation and some of this chemistry has been transferred to the solid phase or adapted for programmable one pot synthesis approaches.

Exploring the Galectin Network by Light and Fluorescence Microscopy.

Dynamic changes of a cell's glycophenotype are increasingly interpreted as shifts in the capacity to interact with tissue (endogenous) lectins. The status of glycan branching or chain length (e.g.

Cyclisations and Strategies for Stereoselective Synthesis of Piperidine Iminosugars.

This personal account focuses on synthesis of polyhydroxylated piperidines, a subset of compounds within the iminosugar family. Cyclisations to form the piperidine ring include reductive amination, substitution via amines, iminium ions and cyclic nitrones, transamidification (N-acyl transfer), addition to alkenes, ring contraction and expansion, photoinduced electron transfer, multicomponent Ugi reaction and ring closing metathesis. Enantiomerically pure piperidines are obtained from chiral pool precursors (e.

What is the Sugar Code?

A code is defined by the nature of the symbols, which are used to generate information-storing combinations (e. g. oligo- and polymers).

Immunomodulatory properties of characellide A on human peripheral blood mononuclear cells.

Marine sponges and their associated microbiota are multicellular animals known to produce metabolites with interesting pharmacological properties playing a pivotal role against a plethora of pathologic disorders such as inflammation, cancer and infections. Characellide A and B belong to a novel class of glycolipopeptides isolated from the deep sea marine sponge Characella pachastrelloides. In this study, we have evaluated the effects of characellide A and B on cytokine and chemokine release from human peripheral blood mononuclear cells (PBMC).

Imitating evolution's tinkering by protein engineering reveals extension of human galectin-7 activity.

Wild-type lectins have distinct types of modular design. As a step to explain the physiological importance of their special status, hypothesis-driven protein engineering is used to generate variants. Concerning adhesion/growth-regulatory galectins, non-covalently associated homodimers are commonly encountered in vertebrates.

Crystal Structure of the Carbohydrate Recognition Domain of the Human Macrophage Galactose C-Type Lectin Bound to GalNAc and the Tumor-Associated Tn Antigen.

The human macrophage galactose lectin (MGL) is an endocytic type II transmembrane receptor expressed on immature monocyte-derived dendritic cells and activated macrophages and plays a role in modulating the immune system in response to infections and cancer. MGL contains an extracellular calcium-dependent (C-type) carbohydrate recognition domain (CRD) that specifically binds terminal acetylgalactosamine glycan residues such as the Tn and sialyl-Tn antigens found on tumor cells, as well as other and glycans displayed on certain viruses and parasites. Even though the glycan specificity of MGL is known and several binding glycoproteins have been identified, the molecular basis for substrate recognition has remained elusive due to the lack of high-resolution structures.

Probing sulfatide-tissue lectin recognition with functionalized glycodendrimersomes.

The small 3--sulfated galactose head group of sulfatides, an abundant glycosphingolipid class, poses the (sphinx-like) riddle on involvement of glycan bridging by tissue lectins (sugar code). First, synthesis of head group derivatives for functionalization of amphiphilic dendrimers is performed. Aggregation of resulting (biomimetic) vesicles, alone or in combination with lactose, demonstrates bridging by a tissue lectin (galectin-4).

Development of Mcl-1 inhibitors for cancer therapy.

The myeloid leukemia cell differentiation protein (Mcl-1) is an anti-apoptotic protein of the B-cell lymphoma 2 (Bcl-2) family, which regulates cellular apoptosis. Mcl-1 expression plays a key role in survival of cancer cells and therefore serves as a promising target in cancer therapy. Besides, its importance as a cancer target, various peptides and small-molecule inhibitors have been successfully designed and synthesized, yet no Mcl-1 inhibitor is approved for clinical use.

Microcavity array supported lipid bilayer models of ganglioside - influenza hemagglutinin binding.

The binding of influenza receptor (HA1) to membranes containing different glycosphingolipid receptors was investigated at Microcavity Supported Lipid Bilayers (MSLBs). We observed that HA1 preferentially binds to GD1a but the diffusion coefficient of the associated complex at lipid bilayer is approximately double that of the complexes formed by HA1 GM1 or GM3.

Correction to: Influence of protein (human galectin-3) design on aspects of lectin activity.

In the original publication of the article, the "Result" section has been published.

Influence of protein (human galectin-3) design on aspects of lectin activity.

The concept of biomedical significance of the functional pairing between tissue lectins and their glycoconjugate counterreceptors has reached the mainstream of research on the flow of biological information. A major challenge now is to identify the principles of structure-activity relationships that underlie specificity of recognition and the ensuing post-binding processes. Toward this end, we focus on a distinct feature on the side of the lectin, i.

Microcavity-Supported Lipid Membranes: Versatile Platforms for Building Asymmetric Lipid Bilayers and for Protein Recognition.

Microcavity-supported lipid bilayers (MSLBs) are contact-free membranes suspended across aqueous-filled pores that maintain the lipid bilayer in a highly fluidic state, free from frictional interactions with substrate. Such platforms offer the prospect of liposome-like fluidity with the compositional versatility and addressability of supported lipid bilayers and thus offer a significant opportunity to model membrane asymmetry, protein-membrane interactions, and aggregation at the membrane interface. Herein we evaluate their performance by studying the effect of transmembrane lipid asymmetry on lipid diffusivity, membrane viscosity, and cholera toxin-ganglioside recognition across six symmetric and asymmetric membranes including binary compositions containing both fluid and gel phases, and ternary phase-separated membrane compositions.

Multi-targeting protein-protein interaction inhibitors: Evolution of macrocyclic ligands with embedded carbohydrates (MECs) to improve selectivity.

Compounds targeting multiple proteins can have synergistic effects and are therefore of interest in medicinal chemistry. At the same time, inhibiting protein-protein interactions (PPI) is increasingly desired in the treatment of disorders or diseases. The development of non-peptidomimetic inhibitors is still a challenge.

How altering the modular architecture affects aspects of lectin activity: case study on human galectin-1.

Discoveries on involvement of glycan-protein recognition in many (patho)physiological processes are directing attention to exploring the significance of a fundamental structural aspect of sugar receptors beyond glycan specificity, i.e., occurrence of distinct types of modular architecture.