Kuettel, Sabine; Mosimann, Marc; Mäser, Pascal; Kaiser, Marcel; Brun, Reto; Scapozza, Leonardo; Perozzo, Remo (2009). Adenosine Kinase of T. b. Rhodesiense identified as the putative target of 4-[5-(4-phenoxyphenyl)-2H-pyrazol-3-yl]morpholine using chemical proteomics. PLoS neglected tropical diseases, 3(8), e506. San Francisco, Calif.: Public Library of Science 10.1371/journal.pntd.0000506
Full text not available from this repository. (Request a copy)BACKGROUND: Human African trypanosomiasis (HAT), a major parasitic disease spread in Africa, urgently needs novel targets and new efficacious chemotherapeutic agents. Recently, we discovered that 4-[5-(4-phenoxyphenyl)-2H-pyrazol-3-yl]morpholine (compound 1) exhibits specific antitrypanosomal activity with an IC(50) of 1.0 microM on Trypanosoma brucei rhodesiense (T. b. rhodesiense), the causative agent of the acute form of HAT. METHODOLOGY/PRINCIPAL FINDINGS: In this work we show adenosine kinase of T. b. rhodesiense (TbrAK), a key enzyme of the parasite purine salvage pathway which is vital for parasite survival, to be the putative intracellular target of compound 1 using a chemical proteomics approach. This finding was confirmed by RNA interference experiments showing that down-regulation of adenosine kinase counteracts compound 1 activity. Further chemical validation demonstrated that compound 1 interacts specifically and tightly with TbrAK with nanomolar affinity, and in vitro activity measurements showed that compound 1 is an enhancer of TbrAK activity. The subsequent kinetic analysis provided strong evidence that the observed hyperactivation of TbrAK is due to the abolishment of the intrinsic substrate-inhibition. CONCLUSIONS/SIGNIFICANCE: The results suggest that TbrAK is the putative target of this compound, and that hyperactivation of TbrAK may represent a novel therapeutic strategy for the development of trypanocides.
Item Type: |
Journal Article (Original Article) |
|---|---|
Division/Institute: |
08 Faculty of Science > Department of Biology > Institute of Cell Biology |
UniBE Contributor: |
Mosimann, Marc, Mäser, Pascal |
ISSN: |
1935-2727 |
Publisher: |
Public Library of Science |
Language: |
English |
Submitter: |
Factscience Import |
Date Deposited: |
04 Oct 2013 15:21 |
Last Modified: |
05 Dec 2022 14:25 |
Publisher DOI: |
10.1371/journal.pntd.0000506 |
Web of Science ID: |
000269220900006 |
URI: |
https://boris.unibe.ch/id/eprint/36699 (FactScience: 205893) |
Actions (login required)
 |
Edit item |