Publications by authors named "John S Brimacombe"
Article Synopsis
- * The filamentous fungus Aspergillus fumigatus produces GPI-anchored molecules vital for its cell wall, and researchers conducted in vitro assays to understand its GPI biosynthesis in the mycelium form of the fungus.
- * The study revealed unique mannosylation processes and compared findings to those in mammals and yeast, establishing that A. fumigatus has similar GPI biosynthetic pathways, with most genes related to this process conserved from Sacchar
Article Synopsis
- Compounds that target glycosylphosphatidylinositol (GPI) biosynthesis are considered effective against the Trypanosoma brucei parasite responsible for sleeping sickness.
- Researchers developed cell-permeable GPI analogues that are toxic to T. brucei but safe for human cells, indicating selective targeting.
- This study provides evidence that the GPI biosynthetic pathway is a viable drug target, potentially leading to new inhibitor discovery from both natural and synthetic sources.
Syntheses are described of 2-azido-4,6-di-O-benzyl-2,3-dideoxy-d-ribo-hexopyranosyl fluoride, 6-O-acetyl-2-azido-3-O-benzyl-2,4-dideoxy-d-xylo-hexopyranosyl fluoride and 2-azido-3,4-di-O-benzyl-2,6-dideoxy-d-glucopyranosyl fluoride. These glycosyl donors were coupled with the acceptor 1d-2,3,4,5-tetra-O-benzyl-1-O-(4-methoxybenzyl)-myo-inositol and the alpha-coupled products were transformed into alpha-d-3dGlcpN-PI, alpha-d-4dGlcpN-PI and alpha-d-6dGlcpN-PI by way of the H-phosphonate route. Brief mention is made of the biological evaluation of these deoxy-sugar analogues and their N-acetylated forms as candidate substrate/inhibitors of the N-deacetylase and alpha-(1-->4)-d-mannosyltransferase activities present in trypanosomal and HeLa (human) cell-free system.
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- - The study describes the preparation and testing of several complex compounds as potential inhibitors of specific enzymes (alpha-(1 --> 4)-D-mannosyltransferases) involved in the GPI biosynthetic pathway in Trypanosoma brucei and human HeLa cells.
- - Various substrate analogues, including N-acetyl derivatives and derivatives of myo-inositol, were created to explore their efficacy in inhibiting these relevant enzymes.
- - Additionally, the research includes a summary of the biological evaluations of these compounds, particularly focusing on their effectiveness as inhibitors based on earlier studies.
A series of synthetic analogues of d-GlcN alpha 1-6-d-myo-inositol-1-HPO(4)-sn-1,2-dipalmitoylglycerol, consisting of 22 variants of the d-GlcN or lipid components, were tested in trypanosomal and human (HeLa) cell-free systems. The assays measured the abilities of the analogues to act as substrates or inhibitors of the enzymes of glycosylphosphatidylinositol biosynthesis downstream of GlcNAc-phosphatidylinositol (GlcNAc-PI) de-N-acetylase. One compound, 4-deoxy-d-GlcN alpha 1-6-d-myo-inositol-1-HPO(4)-sn-1,2-dipalmitoylglycerol, proved to be an inhibitor of both the trypanosomal and HeLa pathways, whereas 4-O-methyl-d-GlcN alpha 1-6-d-myo-inositol-1-HPO(4)-sn-1,2-dipalmitoylglycerol and the 4'-epimer, d-GalN-alpha1-6-d-myo-inositol-1-HPO(4)-sn-1,2-dipalmitoylglycerol, were neither substrates nor inhibitors.
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