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Tytuł pozycji:

Cell Cycle Inhibition To Treat Sleeping Sickness.

Tytuł:
Cell Cycle Inhibition To Treat Sleeping Sickness.
Autorzy:
Epting CL; Department of Pediatrics, Northwestern University, Chicago, Illinois, USA .; Department of Pathology, Northwestern University, Chicago, Illinois, USA.
Emmer BT; Department of Pathology, Northwestern University, Chicago, Illinois, USA.; Department of Microbiology-Immunology, Northwestern University, Chicago, Illinois, USA.
Du NY; Department of Pediatrics, Northwestern University, Chicago, Illinois, USA.; Department of Pathology, Northwestern University, Chicago, Illinois, USA.
Taylor JM; Department of Pediatrics, Northwestern University, Chicago, Illinois, USA.; Department of Pathology, Northwestern University, Chicago, Illinois, USA.
Makanji MY; Department of Pediatrics, Northwestern University, Chicago, Illinois, USA.
Olson CL; Department of Pathology, Northwestern University, Chicago, Illinois, USA.
Engman DM; Department of Pathology, Northwestern University, Chicago, Illinois, USA .; Department of Microbiology-Immunology, Northwestern University, Chicago, Illinois, USA.; Department of Pathology and Laboratory Medicine, Cedars Sinai Medical Center, Los Angeles, California, USA.
Źródło:
MBio [mBio] 2017 Sep 19; Vol. 8 (5). Date of Electronic Publication: 2017 Sep 19.
Typ publikacji:
Journal Article; Research Support, Non-U.S. Gov't; Research Support, N.I.H., Extramural
Język:
English
Imprint Name(s):
Original Publication: Washington, D.C. : American Society for Microbiology
MeSH Terms:
Cell Cycle/*drug effects
Enzyme Inhibitors/*therapeutic use
Hydroxyurea/*therapeutic use
Ribonucleotide Reductases/*antagonists & inhibitors
Trypanocidal Agents/*therapeutic use
Trypanosoma brucei brucei/*drug effects
Trypanosomiasis, African/*drug therapy
Animals ; Drug Discovery ; Enzyme Inhibitors/pharmacology ; Humans ; Hydroxyurea/administration & dosage ; Hydroxyurea/pharmacology ; Mice ; Ribonucleotide Reductases/metabolism ; Trypanocidal Agents/pharmacology ; Trypanosoma brucei brucei/enzymology ; Trypanosoma brucei brucei/genetics ; Trypanosoma brucei brucei/physiology ; Trypanosomiasis, African/parasitology
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Grant Information:
F30 HL094026 United States HL NHLBI NIH HHS; R01 HL080692 United States HL NHLBI NIH HHS; UL1 RR025741 United States RR NCRR NIH HHS; UL1 TR001422 United States TR NCATS NIH HHS
Contributed Indexing:
Keywords: African sleeping sickness; Trypanosoma brucei; hydroxyurea; ribonucleotide reductase
Substance Nomenclature:
0 (Enzyme Inhibitors)
0 (Trypanocidal Agents)
EC 1.17.4.- (Ribonucleotide Reductases)
X6Q56QN5QC (Hydroxyurea)
Entry Date(s):
Date Created: 20170921 Date Completed: 20180514 Latest Revision: 20191227
Update Code:
20240104
PubMed Central ID:
PMC5605941
DOI:
10.1128/mBio.01427-17
PMID:
28928213
Czasopismo naukowe
African trypanosomiasis is caused by infection with the protozoan parasite Trypanosoma brucei During infection, this pathogen divides rapidly to high density in the bloodstream of its mammalian host in a manner similar to that of leukemia. Like all eukaryotes, T. brucei has a cell cycle involving the de novo synthesis of DNA regulated by ribonucleotide reductase (RNR), which catalyzes the conversion of ribonucleotides into their deoxy form. As an essential enzyme for the cell cycle, RNR is a common target for cancer chemotherapy. We hypothesized that inhibition of RNR by genetic or pharmacological means would impair parasite growth in vitro and prolong the survival of infected animals. Our results demonstrate that RNR inhibition is highly effective in suppressing parasite growth both in vitro and in vivo These results support drug discovery efforts targeting the cell cycle, not only for African trypanosomiasis but possibly also for other infections by eukaryotic pathogens. IMPORTANCE The development of drugs to treat infections with eukaryotic pathogens is challenging because many key virulence factors have closely related homologues in humans. Drug toxicity greatly limits these development efforts. For pathogens that replicate at a high rate, especially in the blood, an alternative approach is to target the cell cycle directly, much as is done to treat some hematologic malignancies. The results presented here indicate that targeting the cell cycle via inhibition of ribonucleotide reductase is effective at killing trypanosomes and prolonging the survival of infected animals.
(Copyright © 2017 Epting et al.)

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