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Title: N-myristoyltransferase inhibitor binding mode and phenotype in the malarial parasite
Author: Schlott, Anja Christine
ISNI:       0000 0005 0287 2029
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2019
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Malaria continues to be a significant cause of death and morbidity worldwide and there is a need for new antimalarial drugs with novel targets. As a potential target for drug development against malaria, the focus of this thesis is on N-myristoyltransferase (NMT), an enzyme that acylates a wide range of substrate proteins. The NMT substrates in Plasmodium falciparum include proteins that are important in essential processes including parasite signalling pathways, protein transport, and host cell invasion. Myristoylation facilitates the interaction of proteins with membranes, which may be strengthened by further lipidation, and inhibition of NMT results in incorrect protein localization and consequent disruption of function. The diverse roles of NMT substrates mean that NMT inhibition has a pleiotropic and severe impact on parasite development, growth and multiplication. To study the mechanism of action underlying NMT inhibition it is important to consider the function of proteins upstream and downstream of NMT. The phenotype of loss of myristoylation on particular substrates in isolation, through genetic manipulation of the N-terminal glycine, gives insights in the essentiality of this mostly co-translational modification. Because there is an increasing threat of resistance to all front-line drugs against malaria, it is important to study resistance development early in the drug development process. This could aid the selection of drug combinations and impede rapid evolution of parasite resistance. This thesis describes the first parasites resistance mechanism to a particular NMT inhibitor series and shows that resistance in an in vitro parasite growth assay is mediated by a single amino acid substitution in the NMT substrate binding pocket. The basis of resistance was validated and analysed with a structure-guided approach using crystallography, in combination with enzyme activity, stability and surface plasmon resonance-assays, allowing identification of another inhibitor series unaffected by this substitution.
Supervisor: Holder, Anthony ; Tate, Edward ; Fuchter, Matthew ; Blackman, Mike Sponsor: Medicines for Malaria Venture ; Seattle Structural Genomics Center for Infectious Disease (SSGCID) ; Cancer Research UK ; Medical Research Council ; Wellcome Trust
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral