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1.
Chris H. Hill Agnete H. Viuff Samantha J. Spratley Stéphane Salamone Stig H. Christensen Randy J. Read Nigel W. Moriarty Henrik H. Jensen Janet E. Deane 《Chemical science》2015,6(5):3075-3086
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. 相似文献
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Finite groups acting on rings by automorphisms, and group-graded rings are instances of Hopf algebras H acting on H-module algebras A. We study such actions. Let AH = {a ε A¦h · A = (h) a, all h ε H}, the ring of H-invariants, and form the smash product A # H. We study the ring extensions AH A A # H. We prove a Maschke-type theorem for A # H-modules. We form an associated Morita context [AH, A, A, A # H] and use these to get connections between the various rings. 相似文献
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Controlled drug delivery remains a research focus for public health to enhance patient compliance, drug efficiency and reduce
the side effects of drugs. Pectin, an edible plant polysaccharide, has been shown to be useful for the construction of drug
delivery systems for specific drug delivery. Several pectin derived formulations have been developed in our laboratory and
tested in vitro, ex vivo, and in vivo for the ability to deliver bioactive substances for therapeutic purposes in the context of interactions with living tissues.
Pectin derivatives carrying primary amine groups were more mucoadhesive and have shown potential in nasal drug delivery and
other mucosal drug delivery. Pectin derivatives with highly esterified galacturonic acid residues are more hydrophobic and
able to sustain the release of incorporated fragrances for a prolonged duration. Less esterified pectin derivatives are able
to penetrate deeper into the skin and may be useful in aromatherapy formulations. Pectin, in combination with zein, a corn
protein, forms hydrogel beads. The bound zein restricts bead swelling and retains the porosity of the beads; the pectin networks
shield the zein from protease attack. The complex beads are ideal vehicles for colon-specific drug delivery. Studies presented
in this paper indicate the flexibility and possibility to tailor pectin macromolecules into a variety of drug delivery systems
to meet different clinical requirements.
Mention of trade names or commercial products in this article is solely for the purpose of providing specific information
and does not imply recommendation or endorsement by the US Department of Agriculture. 相似文献
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The fluxional molecule Os3(CO)7[P(OMe)3]5 has been prepared from OS3(CO)12 and P(OMe)3 by a combination of thermal and UV irradiation synthetic methods. An investigation by 31P and 13C NMR spectroscopy indicated that the mechanism of fluxionality in this compound probably involves the P(OMe)3 ligand of the Os(CO)3[P(OMe)3] unit moving from one equatorial site to the other via a trigonal twist mechanism. 相似文献