Validating 3-Phosphoinositide Dependent Protein Kinase-1 as a Drug Target in African Trypanosoma

Main Article Content

Namaunga Kasumu Chisompola


Introduction: Human African trypanosomiasis is a parasitic disease that is transmitted to the mammalian host through the bite of an infected tsetse fly of the genus Glossina species. The disease is caused by two species, Trypanosoma brucei gambiense and Trypanosoma brucei rhodesiense, disease outcome is dependent on the infective species. Currently, treatment of African trypanosomiasis is dependent on drugs that are highly toxic and drug resistance has been observed. Therefore, there is a need for development of new drugs and vaccines. The genome of T. brucei has been completely sequenced and analysis of the kinome has revealed 156 eukaryotic protein kinases. One such kinase is a homolog of the mammalian 3-phosphoinositide dependent protein kinase-1 (PDK-1), a member of the AGC family of protein kinases which shares 35% similarity with the human PDK-1.

Methods: In this study, RNA interference of 3-phosphoinositide dependent protein kinase-1 was carried out to investigate the effect of gene knock down on Trypanosoma brucei brucei.

Results: Trypanosoma brucei 3-phosphoinositide-dependent protein kinase-1 is important in T. brucei brucei cell proliferation. Further investigations using DAPI and fluorescence microscopy showed that gene knockdown had an impact on cell phenotype.

Conclusion: RNA interference was effective in knocking down genes corresponding to Trypanosoma brucei 3-phosphoinositide-dependent protein kinase-1. Findings of the study demonstrate that TbPDK-1 is important in cell proliferation in blood stream form Trypanosoma brucei brucei. These results validate TbPDK-1 as a potential drug target for African trypanosomes.

Trypanosomiasis, TbPDK-1, RNAi, gene knock down, protein kinase.

Article Details

How to Cite
Chisompola, N. K. (2020). Validating 3-Phosphoinositide Dependent Protein Kinase-1 as a Drug Target in African Trypanosoma. Asian Journal of Biochemistry, Genetics and Molecular Biology, 4(4), 19-26.
Original Research Article


Franco JR, Cecchi G, Priotto G, Paone M, Diarra A, Grout L, et al. Monitoring the elimination of human African trypanosomiasis at continental and country level: Update to 2018. PLoS Negl Trop Dis. 2020;14(5):e0008261.

WHO. Control and surveillance of human African trypanosomiasis: report of a WHO expert committee. Geneva PP - Geneva: World Health Organization; 2013. (WHO technical report series; no. 984).


Simarro PP, Cecchi G, Paone M, Franco JR, Diarra A, Ruiz JA, et al. The Atlas of human African trypanosomiasis: a contribution to global mapping of neglected tropical diseases. Int J Health Geogr. 2010;9(1):57.


Naula C, Parsons M, Mottram JC. Protein kinases as drug targets in trypanosomes and Leishmania. Biochim Biophys Acta. 2005;1754(1–2):151–9.

Berriman M, Ghedin E, Hertz-Fowler C, Blandin G, Renauld H, Bartholomeu DC, et al. The genome of the African trypanosome Trypanosoma brucei. Science. 2005;309(5733):416–22.

Jones NG, Thomas EB, Brown E, Dickens NJ, Hammarton TC, Mottram JC. Regulators of Trypanosoma brucei cell cycle progression and differentiation identified using a kinome-wide RNAi screen. PLoS Pathog. 2014;10(1): e1003886.

Mora A, Komander D, van Aalten DMF, Alessi DR. PDK1, the master regulator of AGC kinase signal transduction. Semin Cell Dev Biol. 2004;15(2):161–70.

Alessi DR, James SR, Downes CP, Holmes AB, Gaffney PR, Reese CB, et al. Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase Balpha. Curr Biol. 1997;7(4):261–9.

Lawlor MA, Mora A, Ashby PR, Williams MR, Murray-Tait V, Malone L, et al. Essential role of PDK1 in regulating cell size and development in mice. EMBO J [Internet]. 2002; 21(14):3728–38.


Bahia D, Oliveira L, Lima F, Colombo P, Silveira J, Mortara R, et al. The TryPIKinome of five human pathogenic trypanosomatids: Trypanosoma brucei, Trypanosoma cruzi, Leishmania major, Leishmania braziliensis and Leishmania infantum - New tools for designing specific inhibitors. Biochem Biophys Res Commun. 2009;390:963–70.

LaCount DJ, Bruse S, Hill KL, Donelson JE. Double-stranded RNA interference in Trypanosoma brucei using head-to-head promoters. Mol Biochem Parasitol. 2000;111(1):67–76.


Alsford S, Horn D. Single-locus targeting constructs for reliable regulated RNAi and transgene expression in Trypanosoma brucei. Mol Biochem Parasitol. 2008; 161(1):76–9.

Tu X, Wang CC. The involvement of two cdc2-related kinases (CRKs) in Trypanosoma brucei cell cycle regulation and the distinctive stage-specific phenotypes caused by CRK3 depletion. J Biol Chem. 2004; 279(19):20519–28.

Bouteille B, Buguet A. The detection and treatment of human African trypanosomiasis. Res Rep Trop Med [Internet]. 2012;11;3:35–45.


Subramaniam C, Veazey P, Redmond S, Hayes-Sinclair J, Chambers E, Carrington M, et al. Chromosome-wide analysis of gene function by RNA interference in the african trypanosome. Eukaryot Cell. 2006;5(9):1539–49.