BBB webinar: Malcolm Walkinshaw

Malcolm Walkinshaw
Wellcome Centre for Cell Biology, School of Biological Sciences, University of Edinburgh, UK

The talk will cover the development of a series of small molecule inhibitor molecules that target Human African Trypanosomiasis (Sleeping Sickness). The parasite that causes the disease is Trypanosoma brucei which is transmitted by the bite of a tsetse fly into the bloodstream of the mammalian host. The ready availability of glucose in the blood has allowed the parasite to rely solely on the glycolytic pathway for its supply of ATP. We have targeted the T. brucei enzyme phosphofructokinase (TbPFK) and identified a family of small molecules that bind to an allosteric pocket in the enzyme and block activity. The compounds are very fast acting and lack of ATP kills the parasite in a matter of minutes. The molecules have good ADME (absorption, distribution, metabolism, and excretion) and pharmacokinetic properties and oral doses of the compounds effectively cure the disease in a mouse model (1). Leishmania and T. cruzi are related parasites that have evolved intracellular habitats and we have also investigated their glycolytic enzymes as potential drug targets (2, 3). Interestingly, they show important differences in activity and regulation, with AMP having a profound effect on the activation of Leishmania PFK. The role of gluconeogenesis is also critical to the intracellular parasites and we show that AMP also acts as the master key regulating glycolysis versus gluconeogenesis (4).

References:

(1) McNae IW, et al. Fast acting allosteric phosphofructokinase inhibitors block trypanosome glycolysis and cure acute African Trypanosomiasis in mice. Nat Commun. 2021, 12:1052

(2) Fernandes PM, et al. Kinetic and structural studies of Trypanosoma and Leishmania phosphofructokinases show evolutionary divergence and identify AMP as a switch regulating glycolysis versus gluconeogenesis. FEBS J. 2020, 287:2847-61

(3) Fernandes PM, et al. The kinetic characteristics of human and trypanosomatid phosphofructokinases for the reverse reaction. Biochem J. 2019, 476:179-91

(4) Yuan M, et al. Structures of Leishmania fructose-1,6-bisphosphatase reveal species-specific differences in the mechanism of allosteric inhibition. J Mol Biol. 2017, 429:3075-89

Chairperson: Ruth Brenk, Department of Biomedicine