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Title: Myristoyl CoA:protein N-myristoyl transferase : a target for a novel antimalarial drug
Author: Meier, Franziska
ISNI:       0000 0004 2687 0354
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2009
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Malaria, an illness caused by protozoan parasites of the genus Plasmodium, continues to be a key global health issue; around 40% of the world’s population are at risk and more than one million people are killed each year according to the World Health Organisation (WHO). It is transmitted via bites of infected female mosquitoes (Anopheles) and its severest form, falciparum malaria, can lead to death if left untreated. Effective malarial treatment is complex due to drug resistance and socioeconomic issues in many of the most affected areas. An enzyme from the parasite, myristoyl CoA:protein N-myristoyl transferase (NMT), has been identified as a potential target for antimalarial drugs. N-Myristoyl transferase, which catalyses the co-translational transfer of myristic acid to an N-terminal glycine of certain substrate proteins, has been shown to be essential for various pathogens. This thesis demonstrates the design, synthesis and analysis of potential inhibitors of Plasmodium falciparum NMT. Approximately 50 inhibitors with systematic variations based on a benzothiazole scaffold have been synthesised. It is known that these benzothiazoles compete with binding of peptide substrate within the NMT enzyme binding cleft. Differences between the peptide binding pockets of P. falciparum and human NMTs were exploited to design effective and selective new antimalarial treatments. The level of inhibition was measured using SPA that monitors the transfer of 3H-labelled myristoyl CoA to the N-terminus of a polypeptide substrate. A plot of enzyme activity as a function of inhibitor concentration gave inhibition curves from which IC50-values were derived. In vitro tests resulted in four hits with improved activity in the low micromolar region against P. falciparum NMT compared to the lead compound. Nevertheless, the inhibitors were not exceptionally selective over Homo sapiens NMT with an IC50 in the low micromolar region also. Selections of the most promising inhibitors have been tested in vivo and considerable reductions in parasitemia were noted.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral