Inhibitors of Trypanosoma brucei 6-Phosphogluconate Dehydrogenase

Abstract

6-Phosphogluconate dehydrogenase (6PGDH) is the third enzyme of the pentose phosphate pathway. It converts 6- phosphogluconate to ribulose 5-phosphate and concomitantly provides NADPH required for many biosynthetic and detoxification reactions. Its presence has been shown to be essential for growth of bloodstream form Trypanosoma brucei, a parasite responsible for African trypanosomiasis and it may be considered a validated drug target in this protozoan. The structure of the enzyme is known from X-ray crystallographic studies. There appears to be relatively little difference between the active sites of the trypanosomal and human enzymes, although pharmacological analysis shows that selective inhibition of an extensive nature is possible. Work has been carried out on the design of several classes of inhibitors for the T. brucei enzyme that are selective over the same enzyme from mammalian liver. One class comprises sugar derivatives, which mimic the substrate of the catalysed reaction. A second class of more potent inhibitors mimic the transition-state and high-energy intermediates of the enzymatic reaction of 6PGDH. 4-Phospho-D-erythronohydroxamate with a Ki = 10 nM is the compound with the highest affinity for the T. brucei 6PGDH reported to date, and the selectivity of 254-fold over the sheep enzyme is also the highest found. A third class of inhibitors are triphenylmethane derivatives, examples of which also show very pronounced anti-trypanosomal activity. Keywords: African trypanosomiasis, sleeping sickness, 6-phosphogluconate dehydrogenase inhibitors, hydroxamic acid derivatives, highenergy intermediate analogues, transition-state analogues, phosphonate compounds, triphenylmethane derivatives