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

Autor: James Kinkead, Ryan Ritchie, Paul A.M. Michels, Simon N. Pettit, Adrian J. Highton, Jeremy C. Mottram, Elizabeth A. Blackburn, Carol Austin, Martin Walker, Martin A. Wear, Antonio K. Vong, Malcolm D. Walkinshaw, Andrew John Keats, Scott P. Webster, Divya Malik, Nick Gray, Chris Swain, Li-Hsuan Yen, Iain W. McNae, Peter M Fernandes, Jacqueline Dornan, Elmarie Myburgh
Jazyk: angličtina
Rok vydání: 2021
Předmět:
0301 basic medicine
Trypanosoma
Science
030106 microbiology
Allosteric regulation
General Physics and Astronomy
Kaplan-Meier Estimate
Trypanosoma brucei
General Biochemistry
Genetics and Molecular Biology
Article
03 medical and health sciences
Inhibitory Concentration 50
Mice
Structure-Activity Relationship
Allosteric Regulation
parasitic diseases
medicine
Animals
Humans
African trypanosomiasis
Glycolysis
Parasites
Protein Kinase Inhibitors
Multidisciplinary
biology
Tsetse fly
General Chemistry
Hep G2 Cells
medicine.disease
biology.organism_classification
030104 developmental biology
Trypanosomiasis
African
Biochemistry
Phosphofructokinases
Acute Disease
Enzyme mechanisms
Phosphorylation
Parasitology
Structure-based drug design
Protein Multimerization
Pathogens
Trypanosomiasis
Phosphofructokinase
Protein Binding
Zdroj: 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 & Walkinshaw, M D 2021, ' Fast acting allosteric phosphofructokinase inhibitors block trypanosome glycolysis and cure acute African trypanosomiasis in mice ', Nature Communications, vol. 12, no. 1, 1052 . https://doi.org/10.1038/s41467-021-21273-6
Nature Communications
Nature Communications, Vol 12, Iss 1, Pp 1-10 (2021)
ISSN: 2041-1723
Popis: 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.
Glycolytic enzymes are challenging drug targets due to their highly conserved active sites and phosphorylated substrates. Here, the authors identify fast acting allosteric inhibitors of Trypanosoma brucei phosphofructokinase that block trypanosome glycolysis and provide cure evidence in murine model.
Databáze: OpenAIRE
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