N-myristoyltransferase (NMT) is a monomeric enzyme, which is ubiquitous in eukaryotes, catalysing an irreversible co-translational transfer of myristate to a particular set of proteins containing an N-terminal glycine. The work presented in this thesis illustrates the use of synthesised small molecules as a probe to investigate the role of NMT in parasites. Chapter 1 looks at the two parasitic diseases that this project targets: malaria and visceral leishmaniasis, which are caused by Plasmodium falciparum (Pf) and Leishmania donovani (Ld) respectively. Additionally, biological evidence to show that NMT is a promising drug target in these parasites is presented. Chapter 2 describes a piggy-back strategy, which was applied to discover a benzofuran compound with moderate inhibition against PfNMT. This molecule was re-synthesised and then validated as a hit by an optimised scintillant proximity assay. Chapter 3 details the process of drug design based on the inhibition data against PfNMT and structural information of the related enzymes, in which a library of 150 benzofuran analogues was generated. Importantly, the cell inhibition results provided strong evidence to chemically validate NMT as a drug target in P. falciparum, leading to the identification of a lead candidate. Chapter 4 gives the initial structure-activity relationships for LdNMT inhibitors, whereby the whole library of the PfNMT inhibitors was screened against LdNMT. In addition, combined with the parasite inhibition assay, two compounds were determined to be the early lead candidates for LdNMT inhibitors. Chapter 5 provides an overview of the work detailed in this thesis and suggests the future directions that will continue the advancement of this project.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:560609 |
| Date | January 2011 |
| Creators | Yu, Zhiyong |
| Contributors | Leatherbarrow, Robin |
| Publisher | Imperial College London |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://hdl.handle.net/10044/1/10191 |
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