Principal Investigator (PI)
The Foundation is providing £145,027 in support.
Anke Harupa
GSK provides in-kind contributions, including scientific expertise in malaria from supporting scientist in screening, enzymology, medicinal chemistry, in vitro-ex vivo parasite expertise, access to Biosafety Level 3 facilities and to GSK´s collection of proprietary compounds.
The Plasmodium parasite has a complex lifecycle that alternates between extracellular invasive stages and intracellular replicative stages in two hosts, mosquito and man. Once transmitted by a mosquito, the sporozoite form of the parasite infects the liver and generates thousands of merozoites which invade red blood cells, multiply inside them, and egress to infect new red blood cells. Some merozoites develop into gametocytes which are ingested by a mosquito, where they fertilize and eventually produce sporozoites, which completes the lifecycle. The asexual intra-erythrocytic stages are responsible for all clinical symptoms of malaria and are therefore the main focus of drug research. Ideally, novel drugs should target multiple stages of the parasite’s lifecycle to not only treat but also prevent disease and transmission. The enzyme N-myristoyltransferase (NMT) is a potential multi-stage antimalarial drug target as it is expressed throughout the parasite lifecycle. NMT is not unique to Plasmodium but is present in all eukaryotic organisms. It catalyzes the attachment of a myristate to certain substrate proteins, which is important for protein stability and protein association with membranes. A gene-knockout study in P. falciparum suggests that NMT is essential in asexual blood stages, and NMT has been recently validated as a drug target in these stages. Inhibition of NMT resulted in non-infectious parasites, in parts due to the failure to assemble the inner membrane complex, which is a critical structural component for parasite motility and host cell invasion. The objective of our project is to perform a screening of compound libraries to identify selective Plasmodium NMT inhibitors and test their effect on the different lifecycle stages of the parasite with a focus on the parasite’s motility and cell invasion capacities.