NCATS Probe Molecules: Inhibitors of trypanosome PFKListed By : Kyle Brimacombe
NCATS, NIH
CategoryGenePathwayDiseaseMember Organization
Drug Discovery SamplePFKM - phosphofructokinase, muscleInfectious DiseasesNCATS
Human African Trypanosomiasis (HAT), also known as sleeping sickness, is a disease caused by the parasitic protist, Trypanosoma brucei, and is endemic to sub-Saharan Africa. More than 60 million people are estimated to be at risk of HAT infection, and the disease is almost always fatal if left untreated. Limitations of classic therapies, including growing prevalence drug resistance, has highlighted a need for the identification of novel therapies.

The glycolytic enzyme phosphofructokinase (PFK) has been recognized as a potential drug target in T. brucei, as the infectious bloodstream stage of the parasite is solely dependent on the metabolism of glucose for ATP generation, and PFK catalyzes first committed step of glycolysis. The necessity of glycolysis for parasite growth has been confirmed by siRNA-mediated knockdown; a 50% decrease in glycolytic flux was found to be sufficient to significantly decrease parasite viability, further suggesting that inhibition of glycolysis may be a viable strategy for HAT therapy.

In collaboration with Dr. Malcolm Walkinshaw (U of Edinburgh), NCATS worked to develop inhibitors of T. brucei (Tb) and T. cruzi (Tc) PFK for the treatment of HAT. Screening and medicinal chemistry efforts led to the identification of the small molecule probe, ML251, which displays potent nM inhibition of Tb and Tc PFK in vitro, and demonstrates clear competition with F6P, the sugar substrate of PFK.

Advanced characterization of these molecules in follow-up models of trypanosome viability and infection is desired, and NCATS is excited to potentially expand this project to others with interest in the field.

Please contact Ajit Jadhav (ajadhav@mail.nih.gov) and Kyle Brimacombe (brimacombek@mail.nih.gov) at NCGC/NCATS to inquire further.

Relevant Publications:

Walsh MJ, Brimacombe KR, Vásquez-Valdivieso MG, et al. Identification of Selective Inhibitors of Phosphofructokinase as Lead Compounds Against Trypanosomiasis. 2011 Oct 18 [Updated 2013 Feb 25]. In: Probe Reports from the NIH Molecular Libraries Program [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2010-.Available from: http://www.ncbi.nlm.nih.gov/books/NBK154498/

Brimacombe KR, Walsh MJ, Liu L, et al. Identification of ML251, a Potent Inhibitor of T. brucei and T. cruzi Phosphofructokinase. ACS Medicinal Chemistry Letters. 2014;5(1):12-17.
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