Access to Galectin-3 Inhibitors from Chemoenzymatic Synthons

Abstract

Chemo-enzymatic strategies are useful to provide both regio-and stereoselective access to bioactive oligosaccharides. We show herein that a glycosynthase mutant of a Thermus thermophilus -glycosidase can react with unnatural glycosides such as 6-azido-6-deoxy-Dglucose/glucosamine to lead to -D-galactopyranosyl--D-glucopyranoside or -D-galactopyranosyl--2-acetamido-2-deoxy-D-glucopyranoside derivatives bearing a unique azide function. Taking advantage of the orthogonality between the azide and the hydroxyl functional groups, the former was next selectively reacted to give rise to a library of galectin-3 inhibitors. Combining enzyme substrate promiscuity and bioorthogonality thus appears as a powerful strategy to rapidly access to sugar-based ligands. 23 36.86.4 c 36 225 d 24 20.83.4 c a Concentrations were as follows: probe 100 nM, hGal-3 1µM and inhibitors tested in serial dilutions from 800 µM to 10 nM; b Assays were carried out in duplicate; c An independent assay was repeated in duplicate for this derivative and confirmed the Kd value determined in the first experiment; d Kd value might be overestimated as compound 36 precipitated during the assay.

Antibody-mediated neutralization of galectin-3 as a strategy for the treatment of systemic sclerosis

“…Belapectin, a galactoarabino-rhamnogalacturonan polysaccharide polymer with low micromolar binding affinity to both Gal-3 and Gal-1 40 did not meet its primary and secondary endpoints in a phase 2b study in patients with NASH, cirrhosis, and portal hypertension, and was repurposed in a subgroup of patients for the prevention of esophageal varices in NASH cirrhosis 41 (ClinicalTrials.gov NCT04365868). A large number of other approaches have focused on targeting Gal-3 with carbohydrate or noncarbohydrate-based compounds, most having been evaluated in preclinical studies and just a few of them reaching clinical stages in various indications [42][43][44][45] .…”

Biocatalytic Approaches to Building Blocks for Enzymatic and Chemical Glycan Synthesis

“…Glycosynthases obtained through mutagenesis of glycosyl hydrolases (removing/reducing hydrolysis activity) are an attractive alternative to glycosyltransferases as they do not require expensive ND­(M)­P-sugar donors. − The E338G mutant of the Thermus thermophilus glycoside hydrolase ( TT βGly E338G) was successfully used in combination with a glycosyl fluoride donor and C6-modified acceptor for the expeditious synthesis of lactose and lactosamine core thioglycosides (Figure B). , Additionally, β- d -glucuronidase Dt GlcA from Dictyoglomus thermophilum has shown promise as a future thioglycoligase capable of catalyzing the formation of S -glucuronides . Mutation of the catalytic E396 residue to glutamine led to an efficient catalyst for synthesizing a small panel of glucuronic acid thioglycosides and lays a foundation for the synthesis of S -glycoside building blocks …”

Current Progress in the Chemoenzymatic Synthesis of Natural Products

“…The range in size from small monosaccharides to enormous polysaccharides possessing hundreds of glycan units correlates with their variety of biological targets and purposes of sugars. Given their versatility, they are used in multiple fields such as food chemistry, medicinal chemistry, and investigations of fundamental biological processes [ 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 ].…”