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

McNae, I. W. et al. (2021) Fast acting allosteric phosphofructokinase inhibitors block trypanosome glycolysis and cure acute African trypanosomiasis in mice. Nature Communications, 12, 1052. (doi: 10.1038/s41467-021-21273-6) (PMID:33594070) (PMCID:PMC7887271)

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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Ritchie, Mr Ryan and Mottram, Professor Jeremy
• Authors: McNae, I. W., Kinkead, J., Malik, D., Yen, L.-H., Walker, M. K., Swain, C., Webster, S. P., Gray, N., Fernandes, P. M., Myburgh, E., Blackburn, E. A., Ritchie, R., Austin, C., Wear, M. A., Highton, A. J., Keats, A. J., Vong, A., Dornan, J., Mottram, J. C., Michels, P. A. M., Pettit, S., and Walkinshaw, M. D.
• College/School: College of Medical Veterinary and Life Sciences > School of Infection & Immunity
• Journal Name: Nature Communications
• Publisher: Nature Research
• ISSN: 2041-1723
• ISSN (Online): 2041-1723
• Copyright Holders: Copyright © 2021 The Authors
• First Published: First published in Nature Communications 12: 1052
• Publisher Policy: Reproduced under a Creative Commons License

Project Code	Award No	Project Name	Principal Investigator	Funder's Name	Funder Ref	Lead Dept
190800		In vivo screening resource to support drug development in parasitic disease	Jeremy Mottram	Wellcome Trust (WELLCOTR)	104976/Z14/Z	III - Parasitology