Sialic acid C-glycosides with aromatic residues: Investigating enzyme binding and inhibition of Trypanosoma cruzi trans-sialidase

Abstract

Several α-configured C-sialosides were synthesised by cross metathesis and further synthetic derivatisation to obtain ligands for Trypanosoma cruzi trans-sialidase (TcTS), a key enzyme in Chagas disease. Affinities of these compounds to immobilised TcTS were measured by surface plasmon resonance (SPR). The K(D) values thus obtained are in the lower millimolar range and will be discussed. The results show the importance of addressing Tyr(119) and Trp(312) side chains of TcTS in target oriented ligand synthesis, since these amino acids constitute the acceptor binding region in the active site of TcTS. The best ligand showed a significant decrease of TcTS activity in a preliminary NMR based inhibition assay.

Analysis of carbohydrates and glycoconjugates by matrix‐assisted laser desorption/ionization mass spectrometry: An update for 2011–2012

“…As a second-generation iminosugar-based oral glucosidase inhibitor for improving postprandial hyperglycemia 1-Deoxy-D-galactonojirimycins with dansyl capped N-substituents TOF As -galactosidase inhibitors and potential probes for GM1 gangliosidosis affected cell lines D-Galactofuranosyl nitromethanes TOF (DHB) New, non-thermodynamic approach to the synthesis (Vojtech et al, 2011) N-Glycooxazolines, Nglycoaminooxazolines, and N-glycothiazolines TOF One-pot synthesis from glycals -Glycosyl thiols MALDI Synthesis by stereospecific ring-opening of 1,6-anhydrosugars Kdo Derivative TOF Me- ( To investigate ring-opening polymerization (Miao et al, 2011) Sialic acid C-glycosides with aromatic residues R-TOF, FAB, ESI By cross metathesis to obtain ligands for Trypanosoma cruzi trans-sialidase (Meinke et al, 2011) Sulfoquinovose (6-deoxy-6-sulfoglucose) TOF Annual bio-production = 10 10 tons. Shown to be degraded by several bacteria (Denger et al, 2012) Oligosaccharides N-acetyl glucosamine disaccharide with free 3-OH TOF Use of 2,2,2-trichloro-ethoxy carbonyl (Troc) as an amino-and 3-OH-protecting group (Enugala & Marques, 2012) N-Acylated-low molecular weight chitosan TOF Acylated with N-OH-tetradecanoic acid.…”

Anomeric 1,2,3-triazole-linked sialic acid derivatives show selective inhibition towards a bacterial neuraminidase over a trypanosome trans-sialidase

“…Although TcTS is the major parasite virulence factor [ 13 ], there is no nanomolar inhibitor developed to date. The most potent TcTS inhibitors described are non-carbohydrate-based molecules (anthraquinones [ 14 ], chalcones and quinolones [ 15 ]) with low micromolar activity, whereas sialic acid-based analogues typically show high millimolar inhibitory activity [ 16 ], with few exceptions such as a pentaerythritol homoglycocluster reported by the Carvalho group [ 17 ] and a C -sialoside bearing phenylpropyl group at C-2 [ 18 ] ( Figure 1C ). In the context of mimicking the terminal sugars α-ᴅ-Neu5Ac(2,3)-β-ᴅ-Gal of Trypanosoma cruzi mucins to obtain potent TcTS inhibitors, our group previously synthesised a small series of C-2-modified sialic acid bearing a monosaccharide tethered via 1,2,3-triazole ring (sialylmimetic neoglycoconjugates) [ 19 ] that showed 67–91% inhibitory activity at 1 mM.…”

Anomeric 1,2,3-triazole-linked sialic acid derivatives show selective inhibition towards a bacterial neuraminidase over a trypanosome trans-sialidase

“…Although TcTS is the major parasite virulence factor [13], there is no nanomolar inhibitor developed to date. The most potent TcTS inhibitors described are non-carbohydrate-based molecules (anthraquinones [14], chalcones and quinolones [15]) with low micromolar activity, whereas sialic acid-based analogues typically show high millimolar inhibitory activity [16], with few exceptions such as a pentaerythritol homoglycocluster reported by the Carvalho group [17] and a C-sialoside bearing phenylpropyl group at C-2 [18] (Figure 1C). Based on our previous approach with a small series of C-2 modified sialic acid bearing a monosaccharide tethered via 1,2,3-triazole ring (sialylmimetic 3 neoglycoconjugates) [19], which showed 67-91% inhibitory activity at 1mM, we now envisaged replacing the monosaccharide moiety by (hetero)aromatic substituents (Figure 2A) expecting better inhibition with hydrophobic substituents as observed for the high affinity reported for C-sialoside.…”