Trypanosoma brucei Glycogen synthase kinase-3,a target for anti-trypanosomal drug development: A public-private partnership to identify novel leads

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. © 2011 odour et al.