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

• Published in: PLoS neglected tropical diseases 2011-04, Vol.5 (4), p.e1017-e1017
• Main Authors: Oduor, Richard O, Ojo, Kayode K, Williams, Gareth P, Bertelli, Francois, Mills, James, Maes, Louis, Pryde, David C, Parkinson, Tanya, Van Voorhis, Wesley C, Holler, Tod P
• Format: Article
• Language: English
• Subjects: Alzheimer's disease; Antiparasitic agents; Antiprotozoal Agents - isolation & purification; Antiprotozoal Agents - pharmacology; Biology; Cell cycle; Collaboration; Crystallography, X-Ray; Drug Evaluation, Preclinical - methods; Drug therapy; Drugs; Enzyme Inhibitors - isolation & purification; Enzyme Inhibitors - pharmacology; Enzymes; Glycogen; Glycogen Synthase Kinase 3 - antagonists & inhibitors; Glycogen Synthase Kinase 3 - chemistry; Glycogen Synthase Kinase 3 - metabolism; Health aspects; Humans; Infections; Kinases; Medicine; Models, Molecular; Parasites; Parasitic Sensitivity Tests; Physiological aspects; Protein Structure, Tertiary; Proteins; Protozoa; Public private partnerships; Public-Private Sector Partnerships; R&D; Research & development; Tropical diseases; Trypanosoma brucei; Trypanosoma brucei brucei - enzymology; Trypanosomiasis
• ISSN: 1935-2735; 1935-2727; 1935-2735
• DOI: 10.1371/journal.pntd.0001017

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. 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. 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.