CIDR / Seattle Biomed Research Institute

Start : January 2015 | Status : Complete

The scientist: Anke Harupa is a postdoctoral fellow who will focus her research on the discovery of new drugs against malaria through a project titled "Identification of small-molecule inhibitors of Plasmodium NMT”. The project is led by Dr. Alexis Kaushansky, Senior Scientist in the group of Dr. Stefan Kappe at Seattle Biomedical Research Institute. Anke has more than four years of experience in malaria research working in the group of Dr. Kappe, and has numerous publications of scientific relevance.

The sponsor: Seattle Biomedical Research Institute has one of the largest malaria research programs in the United States with a particular focus on molecular biology aspects of the most virulent malaria parasite Plasmodium falciparum, in addition to vaccine discovery efforts focusing on malaria in pregnancy, severe malaria in children and liver-stage malaria.

Foundation funding: The Foundation is providing £ 145,027 in support, together with co-funding from the European Union FP7 program through its COFUND scheme.

GSK’s contribution: GSK is providing 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.

Project Description: 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.