Myristoyl CoA:Protein N-Myristoyl Transferase: A Target for a Novel Antimalarial Drug
Author(s)
Meier, Franziska
Type
Thesis
Abstract
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.
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.
Date Issued
2009-06
Date Awarded
2009-10
Copyright Statement
Attribution NoDerivatives 4.0 International Licence (CC BY-ND)
Creator
Meier, Franziska
Publisher Department
Department of Chemistry
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)