PMID- 33249135
OWN - NLM
STAT- MEDLINE
DCOM- 20210810
LR  - 20210810
IS  - 1464-3405 (Electronic)
IS  - 0960-894X (Linking)
VI  - 32
DP  - 2021 Jan 15
TI  - Design, synthesis, and evaluation of substrate - analogue inhibitors of 
      Trypanosoma cruzi ribose 5-phosphate isomerase type B.
PG  - 127723
LID - S0960-894X(20)30834-9 [pii]
LID - 10.1016/j.bmcl.2020.127723 [doi]
AB  - 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 (K(i) = 5.5 +/- 0.1 muM), 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 
      (IC(50) = 17.40 +/- 1.055 muM). 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.
CI  - Copyright (c) 2020 Elsevier Ltd. All rights reserved.
FAU - Gonzalez, Soledad Natalia
AU  - Gonzalez SN
AD  - Instituto de Investigaciones Biotecnologicas, Universidad Nacional de General San 
      Martin - CONICET (IIBio-UNSAM), Avenida 25 de Mayo y Francia CP (1650), San 
      Martin (Buenos Aires), Argentina.
FAU - Mills, Jonathan J
AU  - Mills JJ
AD  - Department of Chemistry, North Carolina State University, 2620 Yarbrough Drive, 
      Box 8204, Raleigh, NC 27695, USA.
FAU - Maugeri, Dante
AU  - Maugeri D
AD  - Instituto de Investigaciones Biotecnologicas, Universidad Nacional de General San 
      Martin - CONICET (IIBio-UNSAM), Avenida 25 de Mayo y Francia CP (1650), San 
      Martin (Buenos Aires), Argentina.
FAU - Olaya, Christopher
AU  - Olaya C
AD  - Department of Chemistry, North Carolina State University, 2620 Yarbrough Drive, 
      Box 8204, Raleigh, NC 27695, USA.
FAU - Laguera, Breana L
AU  - Laguera BL
AD  - Department of Natural Sciences, University of South Carolina Beaufort, 1 
      University Boulevard, Bluffton, SC 29909, USA.
FAU - Enders, Jeffrey R
AU  - Enders JR
AD  - Molecular Education, Technology and Research Innovation Center (METRIC), North 
      Carolina State University, Raleigh, NC 27695, USA.
FAU - Sherman, Julian
AU  - Sherman J
AD  - Department of Microbiology, New York University School of Medicine, 430 East 
      29(th) Street, New York, NY 10016, USA.
FAU - Rodriguez, Ana
AU  - Rodriguez A
AD  - Department of Microbiology, New York University School of Medicine, 430 East 
      29(th) Street, New York, NY 10016, USA.
FAU - Pierce, Joshua G
AU  - Pierce JG
AD  - Department of Chemistry, North Carolina State University, 2620 Yarbrough Drive, 
      Box 8204, Raleigh, NC 27695, USA.
FAU - Cazzulo, Juan Jose
AU  - Cazzulo JJ
AD  - Instituto de Investigaciones Biotecnologicas, Universidad Nacional de General San 
      Martin - CONICET (IIBio-UNSAM), Avenida 25 de Mayo y Francia CP (1650), San 
      Martin (Buenos Aires), Argentina.
FAU - D'Antonio, Edward L
AU  - D'Antonio EL
AD  - Department of Natural Sciences, University of South Carolina Beaufort, 1 
      University Boulevard, Bluffton, SC 29909, USA. Electronic address: 
      edantonio@uscb.edu.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20201126
PL  - England
TA  - Bioorg Med Chem Lett
JT  - Bioorganic & medicinal chemistry letters
JID - 9107377
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Protozoan Proteins)
RN  - 0 (Trypanocidal Agents)
RN  - EC 5.3.1.- (Aldose-Ketose Isomerases)
RN  - EC 5.3.1.6 (ribosephosphate isomerase)
SB  - IM
MH  - 3T3 Cells
MH  - Aldose-Ketose Isomerases/*antagonists & inhibitors/metabolism
MH  - Animals
MH  - Binding Sites
MH  - Catalytic Domain
MH  - *Drug Design
MH  - Enzyme Inhibitors/*chemistry/metabolism/pharmacology
MH  - Kinetics
MH  - Mice
MH  - Molecular Dynamics Simulation
MH  - Protozoan Proteins/*antagonists & inhibitors/metabolism
MH  - Substrate Specificity
MH  - Trypanocidal Agents/*chemical synthesis/metabolism/pharmacology
MH  - Trypanosoma cruzi/drug effects/*enzymology
OTO - NOTNLM
OT  - Amastigote
OT  - Chagas' disease
OT  - Competitive inhibition
OT  - Isomerase
OT  - Neglected tropical diseases
OT  - Substrate-analogue inhibitors
OT  - Trypanosoma cruzi
OT  - Trypomastigote
OT  - Trypsin digestion LC-MS/MS
EDAT- 2020/11/30 06:00
MHDA- 2021/08/11 06:00
CRDT- 2020/11/29 20:29
PHST- 2020/09/22 00:00 [received]
PHST- 2020/11/17 00:00 [revised]
PHST- 2020/11/23 00:00 [accepted]
PHST- 2020/11/30 06:00 [pubmed]
PHST- 2021/08/11 06:00 [medline]
PHST- 2020/11/29 20:29 [entrez]
AID - S0960-894X(20)30834-9 [pii]
AID - 10.1016/j.bmcl.2020.127723 [doi]
PST - ppublish
SO  - Bioorg Med Chem Lett. 2021 Jan 15;32:127723. doi: 10.1016/j.bmcl.2020.127723. 
      Epub 2020 Nov 26.