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

Abstract

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 FindingsA 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/SignificanceWe 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.

Identification and Characterization of Hundreds of Potent and Selective Inhibitors of Trypanosoma brucei Growth from a Kinase-Targeted Library Screening Campaign

“…These target families include phosphodiesterases 11], histone deacetylases 12], and kinases 13,14,15,16,17].…”

Selective Inhibitors of Protozoan Protein N-myristoyltransferases as Starting Points for Tropical Disease Medicinal Chemistry Programs

“…Numerous targets have been assessed, including pyrimidine biosynthesis [16], nucleotide signalling [17], kinase pathways [18] and lipidation [19]. Inhibition of prenylation has shown potential to treat malaria and more recently, lipid modification through inhibition of N -myristoylation has shown encouraging progress.…”

Selection of Molecular Targets for Drug Development Against Trypanosomatids

“…Apart from the essentiality in the life-cycle of trypanosomatid parasites, parasitic GSK-3s has many desirable characteristics that justify its selection as a drug target. More importantly, inhibitor scaffolds and inhibitors of parasitic GSK-3 have been identifi ed that also show good antiparasitic activity (Oduor et al 2011 ;Ojo et al 2011Ojo et al , 2008Xingi et al 2009 ). Indirubins, a class of bis-indole compounds known for over a century as a minor constituent of plant, animal and microorganism-derived indigo, represent inhibitory scaffolds targeting Ld GSK-3s (Xingi et al 2009 ).…”

“…To this end, a collaborative industrial/academic partnership facilitated by the World Health Organization Tropical Diseases Research division (WHO TDR) was initiated, to stimulate research aimed at identifying new drugs for treating HAT. In this context, a subset of 16,000 inhibitors that target human GSK-3β from the Pfi zer compound collection were screened, and potent and selective inhibitors of Tb GSK-3s were identifi ed (Oduor et al 2011 ).…”

“…The T . brucei GSK-3s has provided an excellent example for this strategy and the screening of a compound library from the Pfi zer compound collection as mentioned above, known to target mammalian GSK-3β,resulted in the identifi cation of inhibitors that target better the parasitic Tb GSK-3s (Oduor et al 2011 ).…”