Design, synthesis, and evaluation of substrate - analogue inhibitors of Trypanosoma cruzi ribose 5-phosphate isomerase type B
| Autor: | Juan José Cazzulo, Christopher Olaya, Edward L. D'Antonio, Julian Sherman, Dante A. Maugeri, Jonathan J. Mills, Soledad Natalia Gonzalez, Joshua G. Pierce, Breana L. Laguera, Ana Rodriguez, Jeffrey R. Enders |
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| Rok vydání: | 2020 |
| Předmět: |
Trypanosoma cruzi
Clinical Biochemistry Protozoan Proteins Pharmaceutical Science Isomerase Pentose phosphate pathway Molecular Dynamics Simulation 01 natural sciences Biochemistry Substrate Specificity chemistry.chemical_compound Mice Non-competitive inhibition Catalytic Domain Drug Discovery Ribose Animals Nucleotide Enzyme Inhibitors Molecular Biology Aldose-Ketose Isomerases chemistry.chemical_classification Binding Sites 010405 organic chemistry Organic Chemistry 3T3 Cells Trypanocidal Agents 0104 chemical sciences 010404 medicinal & biomolecular chemistry Kinetics Ribose-5-phosphate isomerase chemistry Drug Design Nucleic acid Iodoacetamide Molecular Medicine |
| Zdroj: | Bioorganicmedicinal chemistry letters. 32 |
| ISSN: | 1464-3405 |
| Popis: | Ribose 5-phosphate isomerase type B (RPI-B) is a key enzyme of the pentose phosphate pathway that catalyzes the isomerization of ribose 5-phosphate (R5P) and ribulose 5-phosphate (Ru5P). Trypanosoma cruzi RPI-B (TcRPI-B) appears to be a suitable drug-target mainly due to: (i) its essentiality (as previously shown in other trypanosomatids), (ii) it does not present a homologue in mammalian genomes sequenced thus far, and (iii) it participates in the production of NADPH and nucleotide/nucleic acid synthesis that are critical for parasite cell survival. In this survey, we report on the competitive inhibition of TcRPI-B by a substrate – analogue inhibitor, Compound B (Ki = 5.5 ± 0.1 μM), by the Dixon method. This compound has an iodoacetamide moiety that is susceptible to nucleophilic attack, particularly by the cysteine thiol group. Compound B was conceived to specifically target Cys-69, an important active site residue. By incubating TcRPI-B with Compound B, a trypsin digestion LC-MS/MS analysis revealed the identification of Compound B covalently bound to Cys-69. This inhibitor also exhibited notable in vitro trypanocidal activity against T. cruzi infective life-stages co-cultured in NIH-3T3 murine host cells (IC50 = 17.40 ± 1.055 μM). The study of Compound B served as a proof-of-concept so that next generation inhibitors can potentially be developed with a focus on using a prodrug group in replacement of the iodoacetamide moiety, thus representing an attractive starting point for the future treatment of Chagas’ disease. |
| Databáze: | OpenAIRE |
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