High-Mannose Oligosaccharide Hemimimetics that Recapitulate the Conformation and Binding Mode to Concanavalin A, DC-SIGN and Langerin.

The "carbohydrate chemical mimicry" exhibited by sp -iminosugars has been utilized to develop practical syntheses for analogs of the branched high-mannose-type oligosaccharides (HMOs) Man and Man . In these compounds, the terminal nonreducing Man residues have been substituted with 5,6-oxomethylidenemannonojirimycin (OMJ) motifs. The resulting oligomannoside hemimimetic accurately reproduce the structure, configuration, and conformational behavior of the original mannooligosaccharides, as confirmed by NMR and computational techniques.

Localization properties of harmonic chains with correlated mass and spring disorder: Analytical approach.

We study the localization properties of normal modes in harmonic chains with mass and spring weak disorder. Using a perturbative approach, an expression for the localization length L_{loc} is obtained, which is valid for arbitrary correlations of the disorder (mass disorder correlations, spring disorder correlations, and mass-spring disorder correlations are allowed), and for practically the whole frequency band. In addition, we show how to generate effective mobility edges by the use of disorder with long range self-correlations and cross-correlations.

Mannobioside biomimetics that trigger DC-SIGN binding selectivity.

Selective DC-SIGN targeting . langerin might lead to anti-infective agents, given their counteracting effects upon infection by some pathogens. Here we show that multivalent sp-iminosugar-containing mannobioside analogs can achieve total DC-SIGN selectivity by levering the canonic binding mode towards high-mannose oligosaccharide ligands, behaving as factual biomimics.

Stereoselective Synthesis of Nojirimycin α--Glycosides from a Bicyclic Acyliminium Intermediate: A Convenient Entry to ,-Biantennary Glycomimetics.

A simple and efficient method for the stereoselective synthesis of nojirimycin α--glycoside derivatives has been developed using a bicyclic carbamate-type sp-iminosugar, whose preparation on a gram scale has been optimized, as the starting material. sp-iminosugar -glycosides or anomeric esters serve as excellent precursors of acyliminium cations, which can add nucleophiles, including -nucleophiles. The stereochemical outcome of the reaction is governed by stereoelectronic effects, affording the target α-anomer with total stereoselectivity.

sp-Iminosugars targeting human lysosomal β-hexosaminidase as pharmacological chaperone candidates for late-onset Tay-Sachs disease.

The late-onset form of Tay-Sachs disease displays when the activity levels of human β-hexosaminidase A (HexA) fall below 10% of normal, due to mutations that destabilise the native folded form of the enzyme and impair its trafficking to the lysosome. Competitive inhibitors of HexA can rescue disease-causative mutant HexA, bearing potential as pharmacological chaperones, but often also inhibit the enzyme O-glucosaminidase (GlcNAcase; OGA), a serious drawback for translation into the clinic. We have designed sp-iminosugar glycomimetics related to GalNAc that feature a neutral piperidine-derived thiourea or a basic piperidine-thiazolidine bicyclic core and behave as selective nanomolar competitive inhibitors of human Hex A at pH 7 with a ten-fold lower inhibitory potency at pH 5, a good indication for pharmacological chaperoning.