Authors

Discussion

Inadequate and antiqued drugs for treating sleeping sickness, a neglected tropical disease caused by the protozoan Trypanosoma brucei (T. brucei), remains a persistent problem across many developing countries. Although several therapies are currently available, their chemotherapeutic targets and mode of action have been poorly elucidated, which has led to low efficacy and a high number of side effects of varying severity.  One chemotherapeutic target, the N-myristoyltransferase (NMT) has received significant attention in recent years and has been validated as drug target against T. brucei; ablating the NMT gene led to cell death and is thus essential for parasite survival. NMT is responsible for the attachment of myristate from myristoyl-CoA to the N-terminal glycine residue of specific proteins. Myristoylation is also required for the remodelling and exchange steps in their essential glycosylphosphatidylinositol (GPI) anchor biosynthesis. Of particular significance is the presence of GPI-anchors in the variant surface glycoproteins coat of T. brucei, an essential virulence factor that plays a crucial role in immune evasion. By synthesizing trypanocidal myristate analogues, it is hoped that these structural mimics will be taken up and utilised by T. brucei, leading to the interference and disruption of their downstream metabolic pathways. This research describes the chemical synthesis of myristate analogues based upon the 14:0 fatty acid chain with some compounds showing EC50 values of <10 µM in the presence of 10 % foetal bovine serum (FBS) and significantly lower EC50 values in lower FBS environments. Subsequent biochemical phenotyping, including lipidomic/metabolomic analyses will elucidate their mode of action.

T. Bayliss et al., J. Med. Chem., 2017, 60, 9790-9806

Y. Hong, T. Kinoshita, Korean J. Parasitol., 2009, 47 (3), 197-204