Chemistry and Biology of Oligovalent β‐(1→2)‐Linked Oligomannosides: New Insights into Carbohydrate‐Based Adjuvants in Immunotherapy

Abstract

A series of oligovalent carbohydrate assemblies (ranging from mono- to pentavalent), derived from three structurally different β-linked or β-(1→2)-linked mannosides, has been chemically synthesized, and the respective compounds have been biologically evaluated in order to investigate their immunostimulatory properties. The Crich methodology for β-mannosylation was successfully utilized to introduce the β-linkages, and a click chemistry protocol was utilized to generate the oligovalent derivatives. A convenient protecting group strategy involving the simultaneous use of both p-methoxybenzyl and benzylidene groups was employed, which allowed a simple and cost-effective global deprotection step. The immunomodulatory properties of the synthesized multivalent mannosides were evaluated by assessing cytokine production in human white blood cell cultures. The Th2-type cytokines interleukin-4 and interleukin-5 (IL-4 and IL-5), the Th1 cytokine interferon-γ (IFN-γ), the Treg cytokine IL-10, and the pro-inflammatory cytokine tumor necrosis factor (TNF) were included in the screening. A single trivalent acetylated mannobiose derivative was identified as a potent inducer of Treg and Th1 immune response, resulting in strong IL-10 and moderate IFN-γ productions dose-dependently, while inducing no Th2 cytokine response. The immunomodulatory properties of this trivalent mannoside were further studied in vitro in allergen (Bet v)-stimulated human peripheral blood mononuclear cell cultures of birch pollen allergic subjects. Stimulation with birch pollen induced strong IL-4 and IL-5 responses, which could be suppressed by the trivalent acetylated mannobiose derivative. The IL-10 response was also suppressed, whereas the production of IFN-γ was strongly enhanced. The results suggest that the identified lead compound has suppressive effects on the Th2-type allergic inflammatory response and shows potential as a possible lead adjuvant for the specific immunotherapy of allergies.

Convergent synthesis of the pentasaccharide repeating unit of the biofilms produced by Klebsiella pneumoniae

“…The target pentasaccharide as its 2-aminoethyl glycoside 1 was synthesized using a set of stereoselective glycosylations of a number of suitably functionalized monosaccharide derivatives 2 , 3 [14], 4 , 5 [15], 6 [16] and 7 [17], which were prepared from the commercially available reducing monosaccharides using a number of functional group manipulations reported earlier (Fig. 1).…”

A novel glycocluster molecule prevents timothy‐induced allergic airway inflammation in mice

“…Triacedimannose is a trivalent glycocluster, consisting of fully acetylated β‐(1→2)‐linked mannobiose units, designed to mimic C. albicans cell wall mannan oligosaccharides, which are known to possess immunostimulatory properties . We have earlier shown in vitro that TADM beneficially affects cytokine production of peripheral blood cells among allergic subjects and favours T helper 1 and T regulatory cell type responses . Previously, we have also shown that, in contrast to CpG and MPLA, TADM does not appear to function as TLR agonist .…”

“…One dosage (50 μL) contained 10 000 SQ (5 μg different timothy allergens of which 2 μg was a major allergen (Phl p 5)). Triacedimannose (1,2,3‐Tris{1‐[(2,3,4,6‐tetra‐ O ‐acetyl‐β‐D‐mannopyranosyl)‐(1→2)‐(3,4,6‐tri‐ O ‐acetyl‐α‐D‐mannopyranosyloxyethyl)]‐4‐(methyl‐1‐oxy)‐1,2,3‐triazolyl}propane) (Figure ) was synthesized as previously described . CpG and synthetic MPLA were purchased from InvivoGen (San Diego, CA, USA).…”

“…Adjuvants are used in allergen preparations in SIT to enhance the effect and modulate the immune response towards Treg and Th1‐type responses. Our recent studies have shown that a synthetic trivalent glycocluster (generated from fully acetylated β‐(1→2)‐linked mannobioses), triacedimannose (TADM) (Figure ), suppresses the Th2‐type allergic inflammatory response . The aim of this study was to compare TADM with two well‐known adjuvants, unmethylated cytosine‐phosphate‐guanine oligodeoxynucleotide (CpG) and monophosphoryl lipid A (MPLA) in a grass allergen‐induced chronic allergic inflammation model in mice.…”

Anomeric O-Functionalization of Carbohydrates for Chemical Conjugation to Vaccine Constructs

“…In 2013, Lin’s group demonstrated thiotolyl mannoside could be coupled with a 6-azidohexyl linker under the activation of NIS/TfOH at low temperature to afford α-6-azidohexyl manoside in good yield [ 83 ] ( Figure 12 , entry 7). On the other hand, a more challenging β-azidoethyl mannoside was synthesized by Leino’s group using Crich’s modified pre-activation [ 84 ] method, which required very careful temperature control [ 85 ] ( Figure 12 , entry 8). Although the yield of the desired product was only 34%, the applicability of this methodology to disaccharide thioglycoside donors is notable.…”