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Antimicrobial Agents and Chemotherapy, October 2008, p. 3710-3717, Vol. 52, No. 10
0066-4804/08/$08.00+0     doi:10.1128/AAC.00364-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Glycogen Synthase Kinase 3 Is a Potential Drug Target for African Trypanosomiasis Therapy{triangledown}

Kayode K. Ojo,1 J. Robert Gillespie,1 Aaron J. Riechers,1 Alberto J. Napuli,2 Christophe L. M. J. Verlinde,2 Frederick S. Buckner,1 Michael H. Gelb,3 Mathias M. Domostoj,4 Susan J. Wells,4 Alexander Scheer,4 Timothy N. C. Wells,4 and Wesley C. Van Voorhis1*

Division of Allergy and Infectious Diseases, Department of Medicine,1 Department of Biochemistry,2 Department of Chemistry, University of Washington, Seattle, Washington 98195,3 Merck-Serono Geneva Research Centre, Merck-Serono International S.A. Chemin des Mines 9, Geneva CH-1202, Switzerland4

Received 16 March 2008/ Returned for modification 26 May 2008/ Accepted 10 July 2008

Development of a safe, effective, and inexpensive therapy for African trypanosomiasis is an urgent priority. In this study, we evaluated the validity of Trypanosoma brucei glycogen synthase kinase 3 (GSK-3) as a potential drug target. Interference with the RNA of either of two GSK-3 homologues in bloodstream-form T. brucei parasites led to growth arrest and altered parasite morphology, demonstrating their requirement for cell survival. Since the growth arrest after RNA interference appeared to be more profound for T. brucei GSK-3 "short" (Tb10.161.3140) than for T. brucei GSK-3 "long" (Tb927.7.2420), we focused on T. brucei GSK-3 short for further studies. T. brucei GSK-3 short with an N-terminal maltose-binding protein fusion was cloned, expressed, and purified in a functional form. The potency of a GSK-3-focused inhibitor library against the recombinant enzyme of T. brucei GSK-3 short, as well as bloodstream-form parasites, was evaluated with the aim of determining if compounds that inhibit enzyme activity could also block the parasites' growth and proliferation. Among the compounds active against the cell, there was an excellent correlation between activity inhibiting the T. brucei GSK-3 short enzyme and the inhibition of T. brucei growth. Thus, there is reasonable genetic and chemical validation of GSK-3 short as a drug target for T. brucei. Finally, selective inhibition may be required for therapy targeting the GSK-3 enzyme, and a molecular model of the T. brucei GSK-3 short enzyme suggests that compounds that selectively inhibit T. brucei GSK-3 short over the human GSK-3 enzymes can be found.

* Corresponding author. Mailing address: Division of Allergy and Infectious Diseases, Department of Medicine, Box 357185, 1959 NE Pacific St., Seattle, WA 98195-7185. Phone: (206) 543-2447. Fax: (206) 685-8681. E-mail: wesley{at}u.washington.edu

{triangledown} Published ahead of print on 21 July 2008.

Antimicrobial Agents and Chemotherapy, October 2008, p. 3710-3717, Vol. 52, No. 10
0066-4804/08/$08.00+0     doi:10.1128/AAC.00364-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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