Identifying new drug targets against African Trypanosomiasis

Abstract

Identifying new drug targets against African Trypanosomiasis Human African Trypanosomiasis (HAT), one of the common tropical neglected diseases (NTDs), is responsible for extensive suffering, death and economic burden in developing countries. NTDs represent the sixth greatest global health burden in terms of the disability adjusted life years. Research and development yielding safe and effective drugs for their treatment and prevention has been recognized as a global health priority. Current drug therapies for HAT are inadequate, hard to administer and have increasing drug resistance problems. To identify and validate new targets for drug discovery we, in a coordinated effort from several groups, are systematically analyzing approximately 200 genes coding for enzymes involved in different biochemical and signaling pathways by RNAi knockdown or gene knockout. We have recently reported the development of a new vector (pTrypRNAiGate) derived from pLEW100 that utilizes the Gateway® recombination system to facilitate easy production of hairpin RNA constructs which facilitates high‐throughput applications for gene silencing and provides a tool for functional genomics in T. brucei. Using this vector we have knocked down 7 aminoacyl tRNA synthetases (AARS), which have an important role in protein translation. RNAi against 5 AARS resulted in growth inhibition of T.brucei bloodstream form in vitro. Two of them, Prolyl tRNA synthetase and Asparagyl tRNA synthetase show morphology changes upon RNAi induction suggesting cell cycle defects. Further validation of AARS, recombinant protein production and assay development is in progress. This work contributes toward a systemic analysis of T. brucei enzymes to identify and validate new drug targets against the infectious disease, African Trypanosomiasis.NIH Grant: AI078962