Peptide probes for Plasmodium falciparum MyoA tail interacting protein (MTIP): exploring the druggability of the malaria parasite motor complex.

Malaria remains an endemic tropical disease and the emergence of Plasmodium falciparum parasites resistant to current front-line medicines means that new therapeutic targets are required. The Plasmodium glideosome is a multi-protein complex that is thought to be essential for efficient host red blood cell invasion. At its core is a myosin motor, Myosin A (MyoA), which provides most of the force required for parasite invasion. Here we report the design and development of improved peptide-based probes for the anchor point of MyoA, P. falciparum MyoA tail interacting protein (PfMTIP). These probes combine low nanomolar binding affinity with significantly enhanced cell penetration and demonstrated competitive target engagement with native PfMTIP demonstrated through a combination of western blot and chemical proteomics. These results provide new insights into the potential druggability of the MTIP/MyoA interaction, and a basis for future design of inhibitors.