Structure-based approach to the identification of a novel group of selective glucosamine analogue inhibitors of Trypanosoma cruzi glucokinase
Abstract
Glucokinase and hexokinase from pathogenic protozoa Trypanosoma cruzi are potential drug targets for antiparasitic chemotherapy of Chagas’ disease. These glucose kinases phosphorylate d-glucose with co-substrate ATP and yield glucose 6-phosphate and are involved in essential metabolic pathways, such as glycolysis and the pentose phosphate pathway. An inhibitor class was conceived that is selective for T. cruzi glucokinase (TcGlcK) using structure-based drug design involving glucosamine having a linker from the C2 amino that terminates with a hydrophobic group either being phenyl, p-hydroxyphenyl, or dioxobenzo[b]thiophenyl groups. The synthesis and characterization for two of the four compounds are presented while the other two compounds were commercially available. Four high-resolution X-ray crystal structures of TcGlcK inhibitor complexes are reported along with enzyme inhibition constants (Ki) for TcGlcK and Homo sapiens hexokinase IV (HsHxKIV). These glucosamine analogue inhibitors include three strongly selective TcGlcK inhibitors and a fourth inhibitor, benzoyl glucosamine (BENZ-GlcN), which is a similar variant exhibiting a shorter linker. Carboxybenzyl glucosamine (CBZ-GlcN) was found to be the strongest glucokinase inhibitor known to date, having a Ki of 0.71 ± 0.05 μM. Also reported are two biologically active inhibitors against in vitro T. cruzi culture that were BENZ-GlcN and CBZ-GlcN, with intracellular amastigote growth inhibitionmore »
- Authors:
-
[3];
- Univ. of South Carolina Beaufort, Bluffton, SC (United States)
- New York Univ. School of Medicine, NY (United States)
- Argonne National Lab. (ANL), Argonne, IL (United States)
- North Carolina State Univ., Raleigh, NC (United States)
- Publication Date:
- Research Org.:
- Argonne National Laboratory (ANL), Argonne, IL (United States)
- Sponsoring Org.:
- USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities Division; US National Institutes of Health; NIH-ORIP HEI
- OSTI Identifier:
- 1251207
- Alternate Identifier(s):
- OSTI ID: 1422460
- Grant/Contract Number:
- AC02-06CH11357; GM103499; P41 GM103403; S10 RR029205
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Molecular and Biochemical Parasitology
- Additional Journal Information:
- Journal Volume: 204; Journal Issue: 2; Journal ID: ISSN 0166-6851
- Publisher:
- Elsevier
- Country of Publication:
- United States
- Language:
- ENGLISH
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; Chagas’ disease; Trypanosoma cruzi; Glucokinase; Hexokinase; Structure-based drug design
Citation Formats
D’Antonio, Edward L., Deinema, Mason S., Kearns, Sean P., Frey, Tyler A., Tanghe, Scott, Perry, Kay, Roy, Timothy A., Gracz, Hanna S., Rodriguez, Ana, and D’Antonio, Jennifer. Structure-based approach to the identification of a novel group of selective glucosamine analogue inhibitors of Trypanosoma cruzi glucokinase. United States: N. p., 2016.
Web. doi:10.1016/j.molbiopara.2015.12.004.
D’Antonio, Edward L., Deinema, Mason S., Kearns, Sean P., Frey, Tyler A., Tanghe, Scott, Perry, Kay, Roy, Timothy A., Gracz, Hanna S., Rodriguez, Ana, & D’Antonio, Jennifer. Structure-based approach to the identification of a novel group of selective glucosamine analogue inhibitors of Trypanosoma cruzi glucokinase. United States. https://doi.org/10.1016/j.molbiopara.2015.12.004
D’Antonio, Edward L., Deinema, Mason S., Kearns, Sean P., Frey, Tyler A., Tanghe, Scott, Perry, Kay, Roy, Timothy A., Gracz, Hanna S., Rodriguez, Ana, and D’Antonio, Jennifer. Thu .
"Structure-based approach to the identification of a novel group of selective glucosamine analogue inhibitors of Trypanosoma cruzi glucokinase". United States. https://doi.org/10.1016/j.molbiopara.2015.12.004. https://www.osti.gov/servlets/purl/1251207.
@article{osti_1251207,
title = {Structure-based approach to the identification of a novel group of selective glucosamine analogue inhibitors of Trypanosoma cruzi glucokinase},
author = {D’Antonio, Edward L. and Deinema, Mason S. and Kearns, Sean P. and Frey, Tyler A. and Tanghe, Scott and Perry, Kay and Roy, Timothy A. and Gracz, Hanna S. and Rodriguez, Ana and D’Antonio, Jennifer},
abstractNote = {Glucokinase and hexokinase from pathogenic protozoa Trypanosoma cruzi are potential drug targets for antiparasitic chemotherapy of Chagas’ disease. These glucose kinases phosphorylate d-glucose with co-substrate ATP and yield glucose 6-phosphate and are involved in essential metabolic pathways, such as glycolysis and the pentose phosphate pathway. An inhibitor class was conceived that is selective for T. cruzi glucokinase (TcGlcK) using structure-based drug design involving glucosamine having a linker from the C2 amino that terminates with a hydrophobic group either being phenyl, p-hydroxyphenyl, or dioxobenzo[b]thiophenyl groups. The synthesis and characterization for two of the four compounds are presented while the other two compounds were commercially available. Four high-resolution X-ray crystal structures of TcGlcK inhibitor complexes are reported along with enzyme inhibition constants (Ki) for TcGlcK and Homo sapiens hexokinase IV (HsHxKIV). These glucosamine analogue inhibitors include three strongly selective TcGlcK inhibitors and a fourth inhibitor, benzoyl glucosamine (BENZ-GlcN), which is a similar variant exhibiting a shorter linker. Carboxybenzyl glucosamine (CBZ-GlcN) was found to be the strongest glucokinase inhibitor known to date, having a Ki of 0.71 ± 0.05 μM. Also reported are two biologically active inhibitors against in vitro T. cruzi culture that were BENZ-GlcN and CBZ-GlcN, with intracellular amastigote growth inhibition IC50 values of 16.08 ± 0.16 μM and 48.73 ± 0.69 μM, respectively. Furthermore, these compounds revealed little to no toxicity against mammalian NIH-3T3 fibroblasts and provide a key starting point for further drug development with this class of compound.},
doi = {10.1016/j.molbiopara.2015.12.004},
journal = {Molecular and Biochemical Parasitology},
number = 2,
volume = 204,
place = {United States},
year = {Thu Jan 14 00:00:00 EST 2016},
month = {Thu Jan 14 00:00:00 EST 2016}
}
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Works referencing / citing this record:
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