Introduction and Background of the Project

Introduction

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).

Project objective

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.

Project design

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.

Final Report

1. Project objective

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 and the number of people who die from malaria, every year more than 600,000 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. The aim of this project was to discover improved compounds suitable for oral single dose treatment of malaria infections. 

2. Project design

Initially the project focused on optimization studies to identify an improved compound with potential for single dose treatment. In a second phase of this project, experiments were planned to determine if it is possible to obtain sufficient levels of compound in the body to treat the malaria infection and to rule out common causes of toxicity at the levels at which the compound will be given. In another aspect of this project, work was planned to prepare the best molecule in sufficiently large quantities for regulatory toxicology studies to show the compound is safe enough to enter human clinical trials. 

3. Results, lessons learned

In this project we developed inhibitors of an enzyme called lysyl t-RNA synthetase as a potential new malaria treatment. This enzyme is critical for all cells to make proteins, essential building blocks in cells. We developed compounds that inhibit this enzyme specifically in the parasites that cause malaria. We demonstrated that inhibitors of this enzyme have the potential for both the treatment of malaria and prevention of malaria. Our most promising molecule can kill malaria parasites at very low concentrations in the laboratory. We determined that the risk of parasites developing resistance to this molecule was relatively low. In early safety studies there were no safety concerns preventing further development. Very encouragingly, it was predicted that this molecule would remain in systemic circulation for long enough to clear malaria infections with a single dose in humans. However, we identified a major shortcoming of our lead molecule: the lack of absorption after oral dosing. This issue needed to be overcome for further progression because new treatments for malaria are required to be oral treatments.

To tackle this problem, we prepared more than 200 molecules designed to have properties known to improve absorption in the gut after oral dosing.  None of these new molecules fulfilled all the requirements for a single dose treatment of malaria. When this initial strategy was deemed exhausted, we explored an alternative approach to identify modified compounds that turn into our lead molecule when they enter the body.  Disappointingly this new approach failed to increase the absorption of the lead molecule. The project team decided to close this project on the bases of these results together with a thorough analysis of alternative strategies and options.

This project was a partnership between Eisai Co., Ltd., Medicines for Malaria Venture, and The Drug Discovery Unit at the University of Dundee. The scientists across these three institutions worked collaboratively bringing expertise in different areas of antimalarial drug discovery and functioning as an integrated project team. There are important learnings arising from this project which will be published in scientific journals and presented at scientific conferences for the benefit of future drug discovery research.