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.     

Rapid convergence of a Galerkin projection of the KdV equation

In this Note, it is shown that a Fourier Galerkin approximation of the Korteweg–de Vries equation with periodic boundary conditions converges exponentially fast if the initial data can be continued analytically to a strip about the real axis. To cite this article: H. Kalisch, C. R. Acad. Sci. Paris, Ser. I 341 (2005).     

Identifying assembly maps in K- and L-theory

In this paper we prove the equivalence of various algebraically or geometrically defined assembly maps used in formulating the main conjectures in K- and L-theory, and C^*-theory.Partially supported by NSERC grant A4000 and NSF grant DMS 9104026. The authors also wish to thank the SFB für Geometrie und Analysis, Münster, and the Max Planck Institut für Mathematik, Bonn, for their hospitality and support.Received: 7 May 2001     

Solutions of the WDVV Equations and Integrable Hierarchies of KP Type

We show that reductions of KP hierarchies related to the loop algebra of SL_n with homogeneous gradation give solutions of the Darboux-Egoroff system of PDE's. Using explicit dressing matrices of the Riemann-Hilbert problem generalized to include a set of commuting additional symmetries, we construct solutions of the Witten– Dijkgraaf–E. Verlinde–H. Verlinde equations.     

Isotopic study of the mechanism of ozone formation

The mechanism of ozone formation has been studied using ¹⁶O and ¹⁸O₂. High-resolution microwave spectroscopy was used to measure the amounts of the isotopomeric ozone species formed. The study is hampered by the very rapid exchange process between the reactants, that tends to scramble the isotopes and hence give a 2:1 statistical ratio between the two possible isotopomers. We have found a strategy to come around this difficulty and conclude that the mechanism is a simple end-on-addition.     

Synthesis of 1-(3-alkyl-2,3-dideoxy-D-pentofuranosyl)uracils with potential anti-HIV activity.

1-(3-Alkyl-2,3-dideoxy-alpha,beta-D-erythro-pentofuranosyl)uracils and 1-(3-alkyl-2,3-dideoxy-alpha,beta-D-threo-pentofuranosyl)uracils have been prepared from (E)-4,5-di-O-acetyl-2,3-dideoxy-aldehydo-D-glycero-pent-2-enose by a Michael addition reaction of the appropriate organocopper reagent followed in subsequent order by glycosidation of the resulting 3-alkyl-4,5-diacetoxypentanal with methanolic hydrogen chloride, protection with p-methoxybenzoyl chloride, and trimethylsilyl triflate catalyzed coupling with 2,4-di-O-(trimethylsilyl)uracil. The nucleosides were deprotected by treatment with 33% methylamine in absolute ethanol and separated by reversed-phase HPLC.     

Representations, convolution square roots and spherical vectors

We extend results on square integrable representations of a locally compact group to subrepresentations of a representations induced from a character of a closed subgroup. We do so working in the framework of quotient representations of ∗-algebras.     

New synthesis of 2',3'-didehydro-2',3'-dideoxynucleosides.

The 3'-iodonucleoside 4 and the 3'-O-methylsulfonylthymidine 9 have been synthesized by condensation of silylated uracils 2 with methyl 5-O-tert-butyldiphensilyl-2,3-dideoxy-3-iodo-D-threo-pentofuran oside (3) and methyl 5-O-tert-butyldiphenylsilyl-2-deoxy-3-methylsulfonyl-D-erythro- pentofuranoside (8), respectively. The nucleoside 4 and 9 produced the corresponding 2',3'-didehydro-2',3'-dideoxynucleosides 5 in an elimination reaction on treatment with sodium methoxide. The compounds 5b showed no antiviral activity against HIV-1.     

Slow-light enhanced optical detection in liquid-infiltrated photonic crystals

Slow-light enhanced optical detection in liquid-infiltrated photonic crystals is theoretically studied. Using a scattering-matrix approach and the Wigner–Smith delay time concept, we show that optical absorbance benefits both from slow-light phenomena as well as a high filling factor of the energy residing in the liquid. Utilizing strongly dispersive photonic crystal structures, we numerically demonstrate how liquid-infiltrated photonic crystals facilitate enhanced light–matter interactions, by potentially up to an order of magnitude. The proposed concept provides strong opportunities for improving existing miniaturized absorbance cells for optical detection in lab-on-a-chip systems.     

The Remainder in Ruijsenaars’ Asymptotic Expansion of Barnes Double Gamma Function

We show that the remainder in Ruijsenaars’ asymptotic expansion of the logarithm of Barnes double gamma function gives rise to a completely monotone function. Fourier expansions of the multiple Bernoulli polynomials are also obtained. Research supported by the Carlsberg Foundation.