1. Academic Validation
  2. Enolase Inhibitors as Early Lead Therapeutics against Trypanosoma brucei

Enolase Inhibitors as Early Lead Therapeutics against Trypanosoma brucei

  • Pathogens. 2023 Oct 28;12(11):1290. doi: 10.3390/pathogens12111290.
Colm P Roster 1 Danielle LaVigne 1 Jillian E Milanes 1 Emily Knight 1 Heidi D Anderson 1 Sabrina Pizarro 1 Elijah M Harding 1 Meredith T Morris 1 Victoria C Yan 2 Cong-Dat Pham 2 Florian Muller 3 Samuel Kwain 4 Kerrick C Rees 4 Brian Dominy 5 Daniel C Whitehead 4 Md Nasir Uddin 2 Steven W Millward 2 James C Morris 1
Affiliations

Affiliations

  • 1 Eukaryotic Pathogens Innovation Center, Department of Genetics and Biochemistry, Clemson University, Clemson, SC 29634, USA.
  • 2 Department of Cancer Systems Imaging, UT MD Anderson Cancer Center, Houston, TX 77030, USA.
  • 3 Sporos Bioventures, 3000 Bissonnet, Belmont Suite 5303, Houston, TX 77005, USA.
  • 4 Eukaryotic Pathogens Innovation Center, Department of Chemistry, Clemson University, Clemson, SC 29634, USA.
  • 5 Department of Chemistry, Clemson University, Clemson, SC 29634, USA.
Abstract

Glucose metabolism is critical for the African trypanosome, Trypanosoma brucei, serving as the lone source of ATP production for the bloodstream form (BSF) Parasite in the glucose-rich environment of the host blood. Recently, phosphonate inhibitors of human Enolase (ENO), the enzyme responsible for the interconversion of 2-phosphoglycerate (2-PG) to phosphoenolpyruvate (PEP) in glycolysis or PEP to 2-PG in gluconeogenesis, have been developed for the treatment of glioblastoma multiforme (GBM). Here, we have tested these agents against T. brucei ENO (TbENO) and found the compounds to be potent enzyme inhibitors and trypanocides. For example, (1-hydroxy-2-oxopyrrolidin-3-yl) phosphonic acid (deoxy-SF2312) was a potent enzyme inhibitor (IC50 value of 0.60 ± 0.23 µM), while a six-membered ring-bearing phosphonate, (1-hydroxy-2-oxopiperidin-3-yl) phosphonic acid (HEX), was less potent (IC50 value of 2.1 ± 1.1 µM). An analog with a larger seven-membered ring, (1-hydroxy-2-oxoazepan-3-yl) phosphonic acid (HEPTA), was not active. Molecular docking simulations revealed that deoxy-SF2312 and HEX had binding affinities of -6.8 and -7.5 kcal/mol, respectively, while the larger HEPTA did not bind as well, with a binding of affinity of -4.8 kcal/mol. None of these compounds were toxic to BSF parasites; however, modification of enzyme-active phosphonates through the addition of pivaloyloxymethyl (POM) groups improved activity against T. brucei, with POM-modified (1,5-dihydroxy-2-oxopyrrolidin-3-yl) phosphonic acid (POMSF) and POMHEX having EC50 values of 0.45 ± 0.10 and 0.61 ± 0.08 µM, respectively. These findings suggest that HEX is a promising lead against T. brucei and that further development of prodrug HEX analogs is warranted.

Keywords

African trypanosome; Trypanosoma brucei; enolase; glycolysis; inhibitors.

Figures
Products