Fast acting allosteric phosphofructokinase inhibitors block trypanosome glycolysis and cure acute African trypanosomiasis in mice

Iain W. McNae, James Kinkead, Divya Malik, Li-Hsuan Yen, Martin K. Walker, Chris Swain, Scott P. Webster, Nick Gray, Peter M. Fernandes, Elmarie Myburgh, Elizabeth A. Blackburn, Ryan Ritchie, Carol Austin, Martin A. Wear, Adrian J. Highton, Andrew J. Keats, Antonio Vong, Jacqueline Dornan, Jeremy C. Mottram, Paul A. M. Michels, Simon Pettit () and Malcolm D. Walkinshaw ()
Additional contact information
Iain W. McNae: University of Edinburgh, Michael Swann Building, Max Born Crescent
James Kinkead: University of Edinburgh, Michael Swann Building, Max Born Crescent
Divya Malik: University of Edinburgh, Michael Swann Building, Max Born Crescent
Li-Hsuan Yen: University of Edinburgh, Michael Swann Building, Max Born Crescent
Martin K. Walker: Selcia Ltd., Fyfield Business and Research Park, Fyfield Road, Ongar
Chris Swain: Cambridge MedChem Consulting
Scott P. Webster: University of Edinburgh
Nick Gray: University of Edinburgh, Michael Swann Building, Max Born Crescent
Peter M. Fernandes: University of Edinburgh, Michael Swann Building, Max Born Crescent
Elmarie Myburgh: University of York
Elizabeth A. Blackburn: University of Edinburgh, Michael Swann Building, Max Born Crescent
Ryan Ritchie: University of Glasgow
Carol Austin: Selcia Ltd., Fyfield Business and Research Park, Fyfield Road, Ongar
Martin A. Wear: University of Edinburgh, Michael Swann Building, Max Born Crescent
Adrian J. Highton: Selcia Ltd., Fyfield Business and Research Park, Fyfield Road, Ongar
Andrew J. Keats: Selcia Ltd., Fyfield Business and Research Park, Fyfield Road, Ongar
Antonio Vong: Selcia Ltd., Fyfield Business and Research Park, Fyfield Road, Ongar
Jacqueline Dornan: University of Edinburgh, Michael Swann Building, Max Born Crescent
Jeremy C. Mottram: University of York
Paul A. M. Michels: University of Edinburgh, Michael Swann Building, Max Born Crescent
Simon Pettit: Selcia Ltd., Fyfield Business and Research Park, Fyfield Road, Ongar
Malcolm D. Walkinshaw: University of Edinburgh, Michael Swann Building, Max Born Crescent

Nature Communications, 2021, vol. 12, issue 1, 1-10

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-21273-6

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