Malaria remains an endemic tropical disease and the emergence of Plasmodium falciparum parasites resistant to current gold-standard medicines means that new therapeutic targets are required. Two separate approaches to discover new therapies and targets are discussed in this thesis. The first approach explores the potential druggability of an essential protein-protein interaction of the invasion machinery, found in the glideosome of the Plasmodium parasite. The Myosin A (MyoA): Myosin A tail interacting protein (MTIP) interaction is thought to provide the motive force required for the invasion of a host cell. This chapter details the design and development of peptide-based probes for the anchor point of this key protein-protein interaction. The peptides displayed low nanomolar binding affinity and were successfully modified to enhance cell penetration. Competitive target engagement with native PfMTIP was demonstrated through a combination of western blot and chemical proteomics. These results provide new insights into the potential druggability of the PfMyoA/PfMTIPinteraction. The second approach builds upon the results of a high-throughput screen which discovered a novel family of compounds with potent activity against Plasmodium male gametocytes. This chapter details the design of photoreactive/clickable analogues of the most potent hit, in order facilitate target-ID experiments. A range of photoreactive moieties were considered, efforts to synthesise the first-choice diazirine bearing
molecules proved unsuccessful. A synthetic route to produce a molecule incorporating alkyne and aryl azide moieties was subsequently developed. The molecule was synthesised, shown to retain low micromolar potency (IC50 = 4.59 mM) against Plasmodium male gametocytes and used in preliminary protein labelling experiments.