Azasugar inhibitors as pharmacological chaperones for Krabbe disease

Krabbe disease is a devastating neurodegenerative disorder characterized by rapid demyelination of nerve fibers. This disease is caused by defects in the lysosomal enzyme β-galactocerebrosidase (GALC), which hydrolyzes the terminal galactose from glycosphingolipids. These lipids are essential components of eukaryotic cell membranes: substrates of GALC include galactocerebroside, the primary lipid component of myelin, and psychosine, a cytotoxic metabolite. Mutations of GALC that cause misfolding of the protein may be responsive to pharmacological chaperone therapy (PCT), whereby small molecules are used to stabilize these mutant proteins, thus correcting trafficking defects and increasing residual catabolic activity in cells. Here we describe a new approach for the synthesis of galacto-configured azasugars and the characterization of their interaction with GALC using biophysical, biochemical and crystallographic methods. We identify that the global stabilization of GALC conferred by azasugar derivatives, measured by fluorescence-based thermal shift assays, is directly related to their binding affinity, measured by enzyme inhibition. X-ray crystal structures of these molecules bound in the GALC active site reveal which residues participate in stabilizing interactions, show how potency is achieved and illustrate the penalties of aza/iminosugar ring distortion. The structure–activity relationships described here identify the key physical properties required of pharmacological chaperones for Krabbe disease and highlight the potential of azasugars as stabilizing agents for future enzyme replacement therapies. This work lays the foundation for new drug-based treatments of Krabbe disease.     

Dichlorocarbene and analogs: discovery,properties and reactions

Russian Chemical Bulletin - The discovery and studies of chemistry of dichlorocarbene and other electron deficient carbenes are discussed.     

On the non existence of monotone linear schema for some linear parabolic equations

In this Note, we present a result concerning the non existence of linear monotone schema with fixed stencil on regular meshes for some linear parabolic equation in two dimensions. The parabolic equations of interest arise from non isotropic diffusion modelling. A corollary is that no linear monotone 9 points-schemes can be designed for the one-dimensional heat equation emerged in the plane with an arbitrary direction of diffusion. Some applications of this result are provided: for the Fokker–Planck–Lorentz model for electrons in the context of plasma physics; all linear monotone scheme for the one-dimensional hyperbolic heat equation treated as a two-dimensional problem are not consistent in the diffusion limit for an arbitrary direction of propagation. We also examine the case of the Landau equation. To cite this article: C. Buet, S. Cordier, C. R. Acad. Sci. Paris, Ser. I 340 (2005).