Peptidomimetic approach to the inhibition of n-myristoyltransferase, a promising parasitic drug target

• Main Author: Olaleye, Tayo
• Format: Dissertation
• Language: English
• Published: ProQuest Dissertations & Theses 01-01-2012

N-myristoyltransferase (NMT), a ubiquitous enzyme, found in a number of organisms including fungi, parasites and humans, catalyses the irreversible transfer of a C-14 chain (myristic acid) to the N-terminal glycine of specific target proteins, a process known as N-myristoylation. NMT has been reported to be essential for the viability of parasites such as Trypanosoma brucei and Leishmania donovani which are responsible for the diseases African sleeping sickness and Leishmaniasis respectively. This suggests that NMT is a promising target for antiparasitic drug development. The work detailed in this thesis describes the use of a piggy-back approach in the design and synthesis of peptidomimetic NMT inhibitors derived from lead compounds originally reported as antifungal NMT inhibitors. NMT, in this report, is explored as a target for the study of malaria and leishmaniasis which are caused by Plasmodium and Leishmania respectively. The current therapeutic treatments of these two diseases, the role of N-myristoylation in the parasitic organisms will be discussed; this thesis will also detail the ligand- and structure-based synthesis of NMT inhibitors using solid phase peptide synthesis. The synthesised inhibitors were tested against P. vivax (PvNMT), P.falciparum (PfNMT), L. donovani (LdNMT) and human enzyme Homo sapiens NMT1 (HsNMT1) using a fluorogenic assay to generate an expansive structure-activity relationship (SAR). A structure- guided methodology using structural information from high resolution crystal structures in both Plasmodium and Leishmania was also employed to rationally design inhibitors. L.majorNMT (LmNMT) was used, for the first time, in a fragment-based screen and 9 hits were attained. Crystal structures of four of the fragments in the library were successfully generated in LmNMT. This work led to the discovery of potent peptidomimetic inhibitors of P. vivax NMT and L. donovani which were design ed from antifungal inhibitors, thus validat ing the piggy-back approach in the study of NMT as a target for malaria and leishmaniasis.