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Trypanosoma brucei Glycogen Synthase Kinase-3, A Target for Anti-Trypanosomal Drug Development: A Public-Private Partnership to Identify Novel Leads.
- Source :
-
PLoS Neglected Tropical Diseases . Apr2011, Vol. 5 Issue 4, p1-8. 8p. 3 Diagrams, 1 Chart, 1 Graph. - Publication Year :
- 2011
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Abstract
- Background: Trypanosoma brucei, the causative agent of Human African Trypanosomiasis (HAT), expresses two proteins with homology to human glycogen synthase kinase 3b (HsGSK-3) designated TbruGSK-3 short and TbruGSK-3 long. TbruGSK- 3 short has previously been validated as a potential drug target and since this enzyme has also been pursued as a human drug target, a large number of inhibitors are available for screening against the parasite enzyme. A collaborative industrial/ academic partnership facilitated by the World Health Organisation Tropical Diseases Research division (WHO TDR) was initiated to stimulate research aimed at identifying new drugs for treating HAT. Methodology/Principal Findings: A subset of over 16,000 inhibitors of HsGSK-3 b from the Pfizer compound collection was screened against the shorter of two orthologues of TbruGSK-3. The resulting active compounds were tested for selectivity versus HsGSK-3b and a panel of human kinases, as well as in vitro anti-trypanosomal activity. Structural analysis of the human and trypanosomal enzymes was also performed. Conclusions/Significance: We identified potent and selective compounds representing potential attractive starting points for a drug discovery program. Structural analysis of the human and trypanosomal enzymes also revealed hypotheses for further improving selectivity of the compounds. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 19352727
- Volume :
- 5
- Issue :
- 4
- Database :
- Academic Search Index
- Journal :
- PLoS Neglected Tropical Diseases
- Publication Type :
- Academic Journal
- Accession number :
- 60797317
- Full Text :
- https://doi.org/10.1371/journal.pntd.0001017