title: Selective inhibition of Trypanosoma brucei GAPDH by 1,3-bisphospho-D-glyceric acid (1,3-diPG) analogues.
abstract: Various phosphono-phosphates and diphosphonates were synthesized as 1,3-diphosphoglycerate (1,3-diPG) analogues by using a beta-ketophosphonate, an alpha-fluoro,beta-ketophosphonate or a beta-ketophosphoramidate to mimic the unstable carboxyphosphate part of the natural substrate. The inhibitory effect of these analogues on glyceraldehyde-3-phosphate dehydrogenases (GAPDH) from Trypanosoma brucei (Tb) and rabbit muscle were measured with respect to both substrates, glyceraldehyde-3-phosphate (GAP) and 1,3-diPG. Interestingly, all 1,5-diphosphono,2-oxopentanes without substitution at the C-3 position selectively inhibit the Tb GAPDH with respect to 1,3-diPG and are without effect on Rm GAPDH. All 1-phospho,3-oxo,4-phosphonobutanes show themselves to be non-selective inhibitors either with regard to substrates or organisms, but they will be of a great interest as 1,3-diPG stable models for structural studies of co-crystals with GAPDHs.
authors: Groupe de Chimie Organique Biologique, LSPCMIB, UMR CNRS 5068, Université Paul Sabatier, Toulouse, France.
authors: S
authors: S
authors: Ladame
authors: M
authors: M
authors: Bardet
authors: J
authors: J
authors: Périé
authors: M
authors: M
authors: Willson
mesh_terms: D000818:Animals; D004163:Diphosphoglyceric Acids / Q000138:chemical synthesis / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020128:Inhibitory Concentration 50; D009132:Muscles / Q000201:enzymology; D011817:Rabbits; D013329:Structure-Activity Relationship; D014344:Trypanocidal Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D014346:Trypanosoma brucei brucei / Q000201:enzymology*
chemical_list: D004163:Diphosphoglyceric Acids; D004791:Enzyme Inhibitors; D014344:Trypanocidal Agents; C015891:glycerate 1,3-biphosphate; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases