Sugar derivatives as new 6-phosphogluconate dehydrogenase inhibitors selective for the parasite Trypanosoma brucei.
Sugar derivatives mimicking compounds which take part in the catalysed reaction have been assayed as alternative substrates and/or competitive inhibitors of 6-phosphogluconate dehydrogenase from Trypanosoma brucei and sheep liver. Phosphonate analogues have been synthesised and the new compound 5-deoxy-5-phosphono-D-arabinonate shows good selectivity towards the parasite enzyme. A number of 4-carbon and 5-carbon aldonates are strong inhibitors of the parasite enzyme with K(i) values below the substrate K(m) and some acyl derivatives are also potent inhibitors. At least five of the compounds showing a significant selectivity for the parasite enzyme represent leads for trypanocidal drugs against this recently validated target.
Pasti
Claudia
C
Dipartimento di Biochimica e Biologia Molecolare, Università di Ferrara, Via L. Borsari 46, 44100, Ferrara, Italy.
Rinaldi
Eliana
E
Cervellati
Carlo
C
Dallocchio
Franco
F
Hardré
Renaud
R
Salmon
Laurent
L
Hanau
Stefania
S
D000818:Animals; D002240:Carbohydrate Sequence; D002241:Carbohydrates / Q000138:chemical synthesis* / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D004926:Escherichia coli / Q000378:metabolism; D007202:Indicators and Reagents; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010734:Phosphogluconate Dehydrogenase / Q000037:antagonists & inhibitors*; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D012756:Sheep; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014344:Trypanocidal Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D014346:Trypanosoma brucei brucei / Q000187:drug effects / Q000201:enzymology*
D002241:Carbohydrates; D004791:Enzyme Inhibitors; D007202:Indicators and Reagents; D011994:Recombinant Proteins; D014344:Trypanocidal Agents; D010734:Phosphogluconate Dehydrogenase