2021 journal article

Design, synthesis, and evaluation of substrate - analogue inhibitors of Trypanosoma cruzi ribose 5-phosphate isomerase type B

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 32.

By: S. Natalia Gonzalez*, J. Mills  n, D. Maugeri*, C. Olaya n, B. Laguera *, J. Enders n , J. Sherman, A. Rodriguez ...

author keywords: Neglected tropical diseases; Chagas' disease; Trypanosoma cruzi; Amastigote; Trypomastigote; Isomerase; Substrate-analogue inhibitors; Competitive inhibition; Trypsin digestion LC-MS/MS
MeSH headings : 3T3 Cells; Aldose-Ketose Isomerases / antagonists & inhibitors; Aldose-Ketose Isomerases / metabolism; Animals; Binding Sites; Catalytic Domain; Drug Design; Enzyme Inhibitors / chemistry; Enzyme Inhibitors / metabolism; Enzyme Inhibitors / pharmacology; Kinetics; Mice; Molecular Dynamics Simulation; Protozoan Proteins / antagonists & inhibitors; Protozoan Proteins / metabolism; Substrate Specificity; Trypanocidal Agents / chemical synthesis; Trypanocidal Agents / metabolism; Trypanocidal Agents / pharmacology; Trypanosoma cruzi / drug effects; Trypanosoma cruzi / enzymology
topics (OpenAlex): Calcium signaling and nucleotide metabolism; Trypanosoma species research and implications; Biochemical and Molecular Research
TL;DR: 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. (via Semantic Scholar)
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Source: Web Of Science
Added: February 8, 2021

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.