- RFP Year2020
- Awarded Amount$3,538,738
- Development StageLead Optimization
- Collaboration PartnersEisai Co., Ltd., Medicines for Malaria Venture (MMV), University of Dundee
Introduction and Background of the Project
Malaria is a major scourge, affecting large parts of the world, in particular Low and Middle Income Countries. Despite recent progress in reducing the number of cases of malaria, every year more than 400,000 people die from this terrible disease, predominantly children under the age of 5 and pregnant women in sub-Saharan Africa. Tackling this disease requires multiple approaches, including new medicines, bed-nets, insecticides and vaccines. In this project we have been developing inhibitors of an enzyme called lysyl tRNA synthetase as a potential new treatment of malaria. This enzyme is critical for all cells to make proteins; essential building blocks in cells. We have developed compounds that inhibit this enzyme specifically in the parasites that cause malaria. We have demonstrated that inhibitors of this enzyme have the potential for both the treatment of malaria and prevention of malaria (chemoprotection).
The aim of this project is to discover improved compounds with potential to treat human infection. In particular we want to identify a compound suitable for single dose treatment of malaria.
The initial part of the project will be further optimization studies to identify an improved molecule with potential for single dose treatment. Work will then focus on profiling the compound to understand it in more detail. This will include a raft of experiments in “test-tubes” and disease models to try and understand if it should be possible to obtain sufficient levels of compound in the body to treat the malaria infection (pharmacokinetics) and experiments to make sure that toxicity is not seen at the levels at which the compound will be given.
How can your partnership (project) address global health challenges?
There is a need for new antimalarials, due to the development of resistance to current drugs and the need for new tools to tackle elimination. Compounds that are active against this target class have the potential to be used for both treatment of blood stage infections and also for chemoprotection. Inhibition of lysyl tRNA synthetase is a novel approach as an antimalarial, which has two key advantages: Firstly, it is unlikely that compounds developed will be cross-resistant to existing anti-malarial drugs. Secondly, it will offer an additional novel mode of action (way of killing malaria) for partnering for combination therapy. It is important to have range of mechanisms for selection of combination partners: all new antimalarial drugs will be combinations. Chemoprotection is a key tool for elimination and drugs which could address this indication will be very valuable for the protection of the most vulnerable populations, most notably pregnant women and children.
What sort of innovation are you bringing in your project?
The enzyme lysyl tRNA synthetase is novel drug target for malaria. Using our knowledge of the enzyme, we have been able to develop inhibitors of the parasite enzyme that are very selective compared to the corresponding human enzyme.
Role and Responsibility of Each Partner
This project has 3 partners, the Drug Discovery Unit at the University of Dundee, Eisai and Medicines for Malaria Venture (MMV).
Dundee’s role will be to carry out the chemistry, computational chemistry, crystallography, enzymology and pharmacology to identify a suitable compound to treat malaria infections. The aim will be to discover a compound which has the potential for single dose treatment of malaria. Dundee will bring their extensive experience in anti-parasitic drug discovery to the project.
Eisai will be involved in profiling the compounds, including pharmacokinetics and safety. Eisai will also develop the chemical route for scale up of the compound to allow preparation of the compound on a large scale. Eisai will also conduct studies to help establish the best way that the compound can be formulated for dosing to patients. Eisai will bring their extensive experience in drug discovery and drug development to the project.
Medicines for Malaria Venture will provide a battery of sophisticated assays to see how effectively the compounds kill both different forms of the parasite and at different stages of the malaria lifecycle. These are all important to understand what doses of compound will be required to treat malaria and how the medicine could be used in the clinic if it progresses that far. MMV will bring their extensive experience in malaria drug discovery and drug development to the project.