A New Generation of Specific <i>Trypanosoma cruzi trans</i>‐Sialidase Inhibitors

Buchini, Sabrina; Buschiazzo, Alejandro; Withers, Stephen G.

doi:10.1002/anie.200705435

Cited by 78 publications

(73 citation statements)

References 12 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…As the aliphatic M-AE linker structure is devoid of UV-absorbing moieties, we had the need to tag its glucose conjugate with a chromophore in order to later monitor the hydrolytic process by HPLC fitted with online UV/Vis detector. This was achieved by subjecting the crude glucoselinker conjugate to one equivalent of N-(benzoyloxy)succinimide [27] (equimolar amounts to linker) in pyridine, thus benzoylating the primary amine. Addition of excess acetic anhydride led to peracetylation of the crude mixture en route to isolation of pure Bz(M-AE)Glc in 22 % overall yield, as described previously for the other linker types (Scheme 3, B).…”

Section: Resultsmentioning

confidence: 99%

Chemoselective Reagents for Covalent Capture and Display of Glycans in Microarrays

2010

View full text Add to dashboard Cite

Glycobiology has made very significant progress in the past decades. However, further progress will significantly depend on the establishment of novel methods for miniaturized, high‐throughput analysis of glycan–protein interactions. Robust solid‐phase chemical tools and new, chemoselective reagents for biologically meaningful display of surface‐immobilized glycans are likely to play a key role. Here we present four new bifunctional linkers that allow highly chemoselective capture of unprotected glycans in solution to form glycan‐linker conjugates for direct construction of glycan microarrays (glycochips). The bifunctional linkers carry O‐linked aminooxy moieties, some with N‐substituents at one end and an amino group at the other. In addition, they contain a substituted benzene ring for UV traceability and improved purification of glycan‐linker conjugates. NMR spectroscopic studies in solution proved that N‐substituted aminooxy linkers provided model glycan‐linker conjugates with the β‐glucopyranoside configuration, i.e. the ring‐closed form required for biological recognition. Then an ensemble of glycan‐linker conjugates were assembled from mannobiose, lactose, and N‐acetyl‐lactosamine and used for covalent printing of glycan microarrays. The stability of oximes were studied both in solution and on‐chip. In solution, two of the linkers provided glycan‐linker conjugates with a remarkable stability at pH 4 or higher, on‐chip this relative stability was upheld. Two of the linkers, with different properties, are recommended for the glycobiology toolbox for the construction of glycan microarrays from unprotected glycans.

show abstract

Section: Resultsmentioning

confidence: 99%

Chemoselective Reagents for Covalent Capture and Display of Glycans in Microarrays

2010

View full text Add to dashboard Cite

show abstract

Section: Commentmentioning

confidence: 99%

“…The altered internal electronic structure in fluorosugars relative to the parent (unsubstituted) saccharide renders them useful for the investigation of enzyme reaction mechanisms, since such substitution can be exploited for the stabilization of putative intermediates along a reaction trajectory (White et al, 1996). In addition, substitution of fluorine for hydroxy groups or H atoms alters the hydrogenbonding character of saccharides, thus affecting their binding properties with various receptors (Buchini et al, 2008).We have been preparing fluorosugars as tools to investigate the mechanisms of protein-bound saccharide rearrangements that accompany non-enzyme-catalyzed protein glycation (Chetyrkin et al, 2008). We reported recently the X-ray crystal structure of 4-deoxy-4-fluoro--d-glucopyranose (4DFG) and showed that its packing and that of the parent -dglucopyranose are very similar (Zhang et al, 2010).…”

mentioning

confidence: 99%

Co-crystals of 3-deoxy-3-fluoro-α-D-glucopyranose and 3-deoxy-3-fluoro-β-D-glucopyranose

2010

View full text Add to dashboard Cite

3-Deoxy-3-fluoro-d-glucopyranose crystallizes from acetone to give a unit cell containing two crystallographically independent molecules. One of these molecules (at site A) is structurally homogeneous and corresponds to 3-deoxy-3-fluoro--d-glucopyranose, C 6 H 11 FO 5 , (I). The second molecule (at site B) is structurally heterogeneous and corresponds to a mixture of (I) and 3-deoxy-3-fluoro--d-glucopyranose, (II); treatment of the diffraction data using partial-occupancy oxygen at the anomeric center gave a high-quality packing model with an occupancy ratio of 0.84:0.16 for (II):(I) at site B. The mixture of -and -anomers at site B appears to be accommodated in the lattice because hydrogen-bonding partners are present to hydrogen bond to the anomeric OH group in either an axial or equatorial orientation. CremerPople analysis of (I) and (II) shows the pyranosyl ring of (II) to be slightly more distorted than that of (I) [ (I) = 3.85 (15) and (II) = 6.35 (16) ], but the general direction of distortion is similar in both structures [' (I) = 67 (2) (B C1,C4 ) and ' (II) = 26.0 (15) ( C3 TB C1 ); B = boat conformation and TB = twistboat conformation]. The exocyclic hydroxymethyl (-CH 2 OH) conformation is gg (gauche-gauche) (H5 anti to O6) in both (I) and (II). Structural comparisons of (I) and (II) to related unsubstituted, deoxy and fluorine-substituted monosaccharides show that the gluco ring can assume a wide range of distorted chair structures in the crystalline state depending on ring substitution patterns. CommentFluorosugars (Taylor, 1988) are saccharide derivatives in which one or more of the hydroxy groups or H atoms in the saccharide are substituted by fluorine. For example, substitution at the anomeric OH group, giving glycosyl fluorides, activates the anomeric center in chemical glycosylation reactions (Yokoyama, 2000). The altered internal electronic structure in fluorosugars relative to the parent (unsubstituted) saccharide renders them useful for the investigation of enzyme reaction mechanisms, since such substitution can be exploited for the stabilization of putative intermediates along a reaction trajectory (White et al., 1996). In addition, substitution of fluorine for hydroxy groups or H atoms alters the hydrogenbonding character of saccharides, thus affecting their binding properties with various receptors (Buchini et al., 2008).We have been preparing fluorosugars as tools to investigate the mechanisms of protein-bound saccharide rearrangements that accompany non-enzyme-catalyzed protein glycation (Chetyrkin et al., 2008). We reported recently the X-ray crystal structure of 4-deoxy-4-fluoro--d-glucopyranose (4DFG) and showed that its packing and that of the parent -dglucopyranose are very similar (Zhang et al., 2010). Furthermore, we showed that the anomeric configuration of 4DFG molecules in the crystal lattice is not completely homogeneous; careful fitting of the electron density at O1 showed that a small percentage (<5%) of the -anomer appears to be accommodated in the lattice. Labeling schem...

show abstract

“…Very recently, inhibition of T. cruzi infection has been achieved by the use of 3-fluorosialyl fluoride, which interferes with the glycosyl-enzyme intermediate [19]. In our study we focused on the role of the N-acyl side chain of sialic acid to inhibit TS activity.…”

Section: Introductionmentioning

confidence: 99%

Invasion of Trypanosoma cruzi into host cells is impaired by N-propionylmannosamine and other N-acylmannosamines

et al. 2011

View full text Add to dashboard Cite

The etiologic agent of Chagas' disease, Trypanosoma cruzi, is widely distributed in South America, affecting millions of people with thousands of deaths every year. Adherence of the infectious trypomastigote to host cells is mediated by sialic acid. T. cruzi cannot synthesize sialic acids on their own but cleave them from the host cells and link them to glycans on the surface of the parasites using the trans-sialidase, a GPI-anchored enzyme. The infectivity of the protozoan parasites strongly depends on the activity of this enzyme. In this report, we investigated whether the transfer of sialic acids from the host to the parasites can be attenuated using novel sialic acid precursors. The cell line 86-HG-39 was infected with T. cruzi and treated with defined N-acylmannosamine analogues bearing an elongated N-acyl side-chain. By treatment of these cells the number of T. cruzi infected cell was reduced up to 60%. We also showed that the activity of the bacterial sialidase C was reduced with N-glycan substrates with elongated N-acyl side chains of the terminal sialic acids. The affinity of this sialidase decreased with the length of the N-acyl side-chain. The data presented suggest that N-acyl modified sialic acid precursors can change the transfer of sialic acids leading to modification of infection. Since the chemotherapy of this disease is inefficient and afflicted by side effects, the need of effective drugs is lasting. These findings propose a new path to prevent the dissemination of T. cruzi in the human hosts. These compounds or further modified analogues might be a basis for the search of new agents against Chagas' disease.

show abstract

A New Generation of Specific Trypanosoma cruzi trans‐Sialidase Inhibitors

Cited by 78 publications

References 12 publications

Chemoselective Reagents for Covalent Capture and Display of Glycans in Microarrays

Chemoselective Reagents for Covalent Capture and Display of Glycans in Microarrays

Co-crystals of 3-deoxy-3-fluoro-α-D-glucopyranose and 3-deoxy-3-fluoro-β-D-glucopyranose

Invasion of Trypanosoma cruzi into host cells is impaired by N-propionylmannosamine and other N-acylmannosamines

Contact Info

Product

Resources

About