Several members of the ADP-ribosylation factor (ARFs) family of the small GTPases are known to be essential for viability in T. brucei bloodstream form cells. However, the molecular interactions of these proteins have not been fully characterised in T. brucei and there is a high level of identity shared between T. brucei and human ARF protein sequences, thus impacting on their potential as drug targets. An alternative method of targeting the ARFs may be through their regulators, the guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs). These regulating molecules are responsible for maintaining the active/inactive state ARFs and are highly divergent in T. brucei. We have identified 7 putative ARF regulators in T. brucei by bioinformatic analysis. We are currently using RNAi to determine whether these proteins are essential in the parasite. Further studies will determine which ARFs are regulated by these proteins, towards development of an assay for inhibitor screening.
