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Title
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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
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Author
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Abstract
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| Background Trypanosoma brucei, the causative agent of Human African Trypanosomiasis (HAT), expresses two proteins with homology to human glycogen synthase kinase 3β (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 β 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-3β 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. |
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Language
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English
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Source (journal)
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PLoS neglected tropical diseases
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Publication
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2011
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ISSN
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1935-2727
1935-2735
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DOI
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10.1371/JOURNAL.PNTD.0001017
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Volume/pages
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5
:4
(2011)
, p. e1017,1-e1017,8
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Article Reference
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e1017
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ISI
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000289937400029
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Medium
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E-only publicatie
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Full text (Publisher's DOI)
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Full text (open access)
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