Nanovesicles displaying functional linear and branched oligomannose self-assembled from sequence-defined Janus glycodendrimers

Abstract

Cell surfaces are often decorated with glycoconjugates that contain linear and more complex symmetrically and asymmetrically branched carbohydrates essential for cellular recognition and communication processes. Mannose is one of the fundamental building blocks of glycans in many biological membranes. Moreover, oligomannoses are commonly found on the surface of pathogens such as bacteria and viruses as both glycolipids and glycoproteins. However, their mechanism of action is not well understood, even though this is of great potential interest for translational medicine. Sequence-defined amphiphilic Janus glycodendrimers containing simple mono- and disaccharides that mimic glycolipids are known to self-assemble into glycodendrimersomes, which in turn resemble the surface of a cell by encoding carbohydrate activity via supramolecular multivalency. The synthetic challenge of preparing Janus glycodendrimers containing more complex linear and branched glycans has so far prevented access to more realistic cell mimics. However, the present work reports the use of an isothiocyanate-amine “click”-like reaction between isothiocyanate-containing sequence-defined amphiphilic Janus dendrimers and either linear or branched oligosaccharides containing up to six monosaccharide units attached to a hydrophobic amino-pentyl linker, a construct not expected to assemble into glycodendrimersomes. Unexpectedly, these oligoMan-containing dendrimers, which have their hydrophobic linker connected via a thiourea group to the amphiphilic part of Janus glycodendrimers, self-organize into nanoscale glycodendrimersomes. Specifically, the mannose-binding lectins that best agglutinate glycodendrimersomes are those displaying hexamannose. Lamellar “raft-like” nanomorphologies on the surface of glycodendrimersomes, self-organized from these sequence-defined glycans, endow these membrane mimics with high biological activity.

Quantifying how step-wise fluorination tunes local solute hydrophobicity, hydration shell thermodynamics and the quantum mechanical contributions of solute–water interactions

“…Tuning hydrophobicity by manipulating hydrogen bonds has been a longstanding goal and challenge in materials science, [8][9][10][11][12][13] organic chemistry [14][15][16] and supramolecular chemistry. [17][18][19][20] However, the usual strategies employed to modify hydrogen bond patterns (the simplest being methylation and hydroxylation) also result in changes in molecular surface area and topology, meaning that water-solute and water-water hydrogen bonds are simultaneously affected. The challenge in such strategies is often perceived as the prediction of which hydrogen bonds are broken, formed or perturbed, and how they will change a solute's hydrophobicity.…”

Bioactive Virus-Mimicking Nanovesicles From Dendrimersomes: A Novel Approach to Understanding SARS-CoV-2 Host-Interactions to Better Design Therapeutics

“…Designing an epitope uniformly on the surface of vesicle manifests singular molecular function and provide a better understanding. The customized design of virus-mimicking nanovesicles has advantages to understand one biomolecular mechanism at a time in a complex viral system (Xiao et al, 2020 ).…”

“…The presence of the surface exposed oligomannose spike S glycoproteins on the surface of the SARS-CoV-2 help them to interact with angiotensin-converting enzyme 2 (ACE2) receptor on the surface of the host cells and mediates entry inside cells (Wang et al, 2020 ; Xiao et al, 2020 ). The special features of the spike S proteins of SARS-CoV-2 make them different from SARS-CoV and provide abilities to evade the host immune system.…”

Enhanced Concanavalin A Binding to Preorganized Mannose Nanoarrays in Glycodendrimersomes Revealed Multivalent Interactions

“…Furthermore, DSs with more complex linear or branched oligosaccharides that mimic those in the cellular surface serve for elucidating glycan‐protein interactions [13a,c, 16] . To investigate the spatial organization of these glycans at the GDSs’ membranes we developed a structural analysis methodology using atomic force microscopy (AFM), [17] fast Fourier transform (FFT) image processing, and molecular modeling [16a, 18] . We discovered that the assembly of sequence‐defined JGDs on which the sugar (lactose (Lac) or oligomannose (oligo(Man))) was diluted in a defined way among tri(ethylene oxide) units in the hydrophilic dendrons gave rise to nanoarrays with the sugar moieties nanoassembled in lamellar or hexagonal patterns [16a, 18] .…”

“…To investigate the spatial organization of these glycans at the GDSs’ membranes we developed a structural analysis methodology using atomic force microscopy (AFM), [17] fast Fourier transform (FFT) image processing, and molecular modeling [16a, 18] . We discovered that the assembly of sequence‐defined JGDs on which the sugar (lactose (Lac) or oligomannose (oligo(Man))) was diluted in a defined way among tri(ethylene oxide) units in the hydrophilic dendrons gave rise to nanoarrays with the sugar moieties nanoassembled in lamellar or hexagonal patterns [16a, 18] . These periodic arrays of glycans reduced the dense packing of Lac and oligo(Man) resulting in faster agglutination in the presence of multidentate lectins [13c, 18] .…”