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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 ( Hs GSK-3) designated  Tbru GSK-3 short and  Tbru GSK-3 long.  Tbru GSK-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  Hs GSK-3 β from the Pfizer compound collection was screened against the shorter of two orthologues of  Tbru GSK-3. The resulting active compounds were tested for selectivity versus  Hs GSK-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.

Trypanosoma brucei Glycogen Synthase Kinase-3, A Target for Anti-Trypanosomal Drug Development: A Public-Private Partnership to Identify Novel Leads