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

Lead Research Organisation: Imperial College London
Department Name: Dept of Chemistry

Abstract

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.

Technical Summary

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.

Publications

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Goncalves V (2012) A fluorescence-based assay for N-myristoyltransferase activity. in Analytical biochemistry

 
Description Doctoral Prize Fellowship (Mark Rackham)
Amount £56,017 (GBP)
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Academic/University
Country United Kingdom
Start 10/2012 
End 09/2013
 
Description Doctoral Prize Fellowship (Megan Wright)
Amount £56,000 (GBP)
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Academic/University
Country United Kingdom
Start 10/2012 
End 09/2012
 
Description EPSRC PhD studentship
Amount £70,000 (GBP)
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Academic/University
Country United Kingdom
Start 10/2011 
End 10/2014
 
Description MMV Development Portfolio
Amount $750,000 (USD)
Organisation Medicines for Malaria Venture (MMV) 
Sector Charity/Non Profit
Country Switzerland
Start 01/2016 
End 12/2017
 
Title Rodent Malaria Data base 
Description This is reasearch data base where all the malaria transgenic parasite information is provided 
Type Of Material Database/Collection of data 
Year Produced 2010 
Provided To Others? Yes  
Impact Many of the mutant are distributed to various researcher across europe and USA 
URL http://www.pberghei.eu/.
 
Title Rodent malaria data base 
Description All the information for phosphatase mutants for malaria model is deposited. It is a rodent malaria transgenic data base 
Type Of Material Database/Collection of data 
Year Produced 2014 
Provided To Others? Yes  
Impact The parasites are provided to different group in France and USA 
URL http://www.pberghei.eu/.
 
Description Anaphase promoting complex 
Organisation University College London
Department UCL Cancer Institute
Country United Kingdom 
Sector Academic/University 
PI Contribution This collaboration is with Prof Hiro Yamano to understand the anaphase promoting complex
Collaborator Contribution Prf Hiro Yamano has contributed immensly for undersyanding of cell division in yeat and mammalian system and provided us with various resources.
Impact We have published one paper together in Plos Pathogenes in 2015
Start Year 2014
 
Description Collaboration on Protein Phosphatases and especially PRL and PTPLA 
Organisation International Centre for Genetic Engineering and Biotechnology
Country Italy 
Sector Charity/Non Profit 
PI Contribution We have provided a training to the student from ICGEB India to learn the reverse genetics in P berghei and understand the parasite stages with mosquito host
Collaborator Contribution The partners are working on PRL in P falciparum.
Impact I am colaborating with computational biologist and the proteomics biologist in this collaboration.
Start Year 2015
 
Description Kinesin in Plasmodium 
Organisation Birkbeck, University of London
Country United Kingdom 
Sector Academic/University 
PI Contribution I am collaborating with Prof Carolyn Moores who is an expert on Kinesin in mammalian system and is a reputed Structural Biologist
Collaborator Contribution She will provide us the biochemistry of of the Kinesin 5 and Kininesin 13
Impact We will be writing the paper at the end of the year.
Start Year 2014
 
Description PKG 
Organisation London School of Hygiene and Tropical Medicine (LSHTM)
Country United Kingdom 
Sector Academic/University 
PI Contribution We have collaborated to generate humanised transgenic parasite to be used as drug target for PKG.
Collaborator Contribution Dr Baker has provided us the human cDNA of PfPKG
Impact We have used this transgenic parasite for testing various compounds and for validation of in vivo assay.
Start Year 2010
 
Description Phosphorylation 
Organisation University of Leicester
Department Department of Cell Physiology and Pharmacology
Country United Kingdom 
Sector Academic/University 
PI Contribution significant intellectual input
Collaborator Contribution To provide technical help with Global Phosphorylationtraining of staff
Impact Two manuscript in preparation
Start Year 2010
 
Description Phosphorylation 
Organisation University of Leicester
Country United Kingdom 
Sector Academic/University 
PI Contribution significant intellectual input
Collaborator Contribution To provide technical help with Global Phosphorylationtraining of staff
Impact Two manuscript in preparation
Start Year 2010
 
Description This collaboration is typrosine phosphatases 
Organisation McGill University
Country Canada 
Sector Academic/University 
PI Contribution WE have published the phosphatome screen in 2014 and described that there are three PTP in Plasmodium and PRL is eesential in Plasmodium,
Collaborator Contribution Prof Michel Tremblay is an expert on Tyrosine phosphatases in mammalian system especialy in relation to cancer.
Impact This collaboration is resulted in collaborating on other collaborator who work in crystallography and chemical biology
Start Year 2015
 
Title Novel compounds and their use in therapy 
Description A novel series of inhibitors of the enzyme N-myristoyltransferase, with therapeutic applications in multiple diseases. 
IP Reference WO2013083991 
Protection Patent application published
Year Protection Granted 2015
Licensed No
Impact Additional funding and collaborations, as noted elsewhere.
 
Title Novel compounds and their use in therapy 
Description This invention relates to compounds for formula (I), (IIA), (IIB), (IIC), (IID), (IIE), (III) and (IV), which are N-myristoyl transferase inhibitors, and to uses of such compounds as medicaments, in particular in the treatment of a disease or disorder in which inhibition of N-myristoyl transferase provides a therapeutic or prophylactic effect. Such diseases include microbial infections, including viral and fungal infections, and hyperproliferative disorders, neurological diseases/disorders, ischemia, osteoporosis and diabetes. Certain compounds of the invention find particular use in the treatment of protozoan infections, for example malaria, leishmaniasis and sleeping sickness. 
IP Reference US20110245460 
Protection Patent application published
Year Protection Granted 2011
Licensed No
Impact Ongoing...