ABSTRACT
The parasitic protist Trypanosoma brucei is the causative agent of Human African Trypanosomiasis, also known as sleeping sickness. The parasite enters the blood via the bite of the tsetse fly where it is wholly reliant on glycolysis for the production of ATP. Glycolytic enzymes have been regarded as challenging drug targets because of their highly conserved active sites and phosphorylated substrates. We describe the development of novel small molecule allosteric inhibitors of trypanosome phosphofructokinase (PFK) that block the glycolytic pathway resulting in very fast parasite kill times with no inhibition of human PFKs. The compounds cross the blood brain barrier and single day oral dosing cures parasitaemia in a stage 1 animal model of human African trypanosomiasis. This study demonstrates that it is possible to target glycolysis and additionally shows how differences in allosteric mechanisms may allow the development of species-specific inhibitors to tackle a range of proliferative or infectious diseases.
Subject(s)
Glycolysis/drug effects , Phosphofructokinases/antagonists & inhibitors , Protein Kinase Inhibitors/pharmacology , Trypanosoma/enzymology , Trypanosomiasis, African/metabolism , Trypanosomiasis, African/parasitology , Acute Disease , Allosteric Regulation/drug effects , Animals , Hep G2 Cells , Humans , Inhibitory Concentration 50 , Kaplan-Meier Estimate , Mice , Parasites/drug effects , Phosphofructokinases/chemistry , Phosphofructokinases/metabolism , Protein Binding/drug effects , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacokinetics , Protein Kinase Inhibitors/therapeutic use , Protein Multimerization , Structure-Activity Relationship , Trypanosoma/drug effects , Trypanosomiasis, African/drug therapyABSTRACT
The development of new antimalarial compounds remains a pivotal part of the strategy for malaria elimination. Recent large-scale phenotypic screens have provided a wealth of potential starting points for hit-to-lead campaigns. One such public set is explored, employing an open source research mechanism in which all data and ideas were shared in real time, anyone was able to participate, and patents were not sought. One chemical subseries was found to exhibit oral activity but contained a labile ester that could not be replaced without loss of activity, and the original hit exhibited remarkable sensitivity to minor structural change. A second subseries displayed high potency, including activity within gametocyte and liver stage assays, but at the cost of low solubility. As an open source research project, unexplored avenues are clearly identified and may be explored further by the community; new findings may be cumulatively added to the present work.
ABSTRACT
Chemistry Central is a new open access website for chemists publishing peer-reviewed research in chemistry from a range of open access journals. A new addition, Chemistry Central Journal, will cover all of chemistry and will be broken down into discipline-specific sections, and Im delighted that Medicinal Chemistry will be a key discipline in this new journal.
