N-Myristoyl Transferase as a drug target for anti-malarial therapy

There is a need to develop new drugs to treat malaria, which is one of the most important global infectious diseases, afflicting hundreds of millions of people each year. We have identified a way to kill the parasite causing malaria using chemical compounds that stop the action of a parasite enzyme that has an important role in allowing the parasite to grow in the blood stream and in passing from one individual to another through the mosquito. What we now plan to do is to make new compounds that are even more effective at killing the parasite so that they can form the basis of the development of new drugs against malaria. To make such improvements we will both look for completely new chemical compounds that work in the same way, and make small changes in the size and shape of the compounds we already have to improve their ability to stop the enzyme from working. To do this improvement work most effectively we need to know the shape and structure of the enzyme and whether or not the compounds can get into the parasite cell to kill it. By understanding how stopping the action of the enzyme kills the parasite we can use the knowledge to develop better ways of testing these potential therapeutics against the parasite in the test tube and within the blood stream. The goal of the project is therefore to confirm that new and better chemical compounds can be developed that are more effective in stopping the action of this enzyme and therefore in killing the parasite that causes malaria. One or more of these compounds may form the basis of a further programme in collaboration with pharmaceutical industry to develop therapeutic drugs.

There is an urgent need for new anti-malarial drugs and for elimination of the disease these must be active against both Plasmodium falciparum and P. vivax, the two most important human malaria parasites. Such drugs should be effective against both the parasite stage responsible for causing disease and against the sexual blood stage that is essential for transmission. We have identified Plasmodium protein:N-myristoyl transferase (NMT) as a suitable target for such drugs and validated it both genetically and chemically. We aim to develop highly effective inhibitors of NMT that are active against the purified enzyme, and will kill the malaria parasite in vitro and in in vivo. Two existing series of inhibitors will be optimised using medicinal chemistry methods and additional leads will be obtained by screening libraries of compounds. Structural studies on the enzyme and inhibitors will inform this process. Active compounds will be screened against P. falciparum asexual blood stages in vitro using a FACS-based assay to identify and select those most active against this parasite. Selected compounds will also be examined for their ability to inhibit gametocytogenesis. We have developed a transgenic rodent malaria parasite, P. berghei that has the P. falciparum NMT gene inserted into the endogenous NMT locus, and this parasite line will be used to screen the efficacy of compounds in vivo against blood stage parasites, including sexual stages. We propose to further validate this model and develop similar parasites transgenic for the P. vivax enzyme so that the efficacy of the inhibitors against this parasite can be evaluated. We will further develop cell biological assays to confirm on-target effects of NMT inhibitors by examining the properties of particular NMT substrates. At the end of the project we will have produced a number of highly active compounds suitable for further drug development in collaboration with Pharma, and provided a clear understanding of the role for NMT in the biology of the malaria parasite.