title: The rational design of trypanocidal drugs: selective inhibition of the glyceraldehyde-3-phosphate dehydrogenase in Trypanosomatidae.
abstract: Within the framework of a project aimed at the structure-based design of drugs for use against sleeping sickness, selective inhibitors were designed, synthesised and tested. The target protein was glycosomal glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and the adenosine part of the NAD cofactor was chosen as lead. After one design cycle and exploiting the selectivity cleft in trypanosomal GAPDH near the C2 of the adenosine ribose, a selective inhibitor, 2'-deoxy-2'-(3-methoxybenzamido)adenosine, was obtained. This compound inhibits human GAPDH only marginally, whereas the enzymes from Trypanosoma brucei and Leishmania mexicana are inhibited by 50% at 2.2 and 0.3 mM, respectively. Moreover, the inhibition of the parasite enzyme is 45-fold (T. brucei) or 170-fold (L. mexicana) greater with this substituted analogue than that produced with adenosine.
authors: Research Unit for Tropical Diseases, International Institute of Cellular and Molecular Pathology, Brussels, Belgium.
authors: M
authors: M
authors: Callens
authors: V
authors: V
authors: Hannaert
mesh_terms: D000818:Animals; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D006801:Humans; D007894:Leishmania mexicana / Q000201:enzymology*; D014344:Trypanocidal Agents / Q000737:chemistry*; D014346:Trypanosoma brucei brucei / Q000201:enzymology*
chemical_list: D004791:Enzyme Inhibitors; D014344:Trypanocidal Agents; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases