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

Abstract

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.