More than half of the world’s population is at risk from infectious diseases such as tuberculosis (TB), malaria, leishmaniasis, Chagas’ disease and human African trypanosomiasis (HAT). Existing treatments can be expensive, difficult to administer, unsafe and increasingly ineffective, as the parasites that underlie these conditions develop resistance. There is therefore an urgent need to develop better, more affordable vaccines and drugs for diseases that are devastating in developing world countries.
Our goal is to generate hit and lead compounds suitable for further development with our partners, and ultimately to identify candidate molecules for entry into pre-clinical development.
In a project funded by Medicines for Malaria Venture (MMV) we identified promising lead anti-malarial compounds by screening our focused protein kinase inhibitor set against malaria parasites. Optimisation of a lead series delivered a highly potent, oral, anti-malarial agent in a rodent model of the disease, which has been approved by MMV for inclusion into their clinical development portfolio. This candidate drug has potential for prevention and single dose treatment of malaria and potentially will block transmission. It is expected to reach the clinic in early 2016.
"Identifying a compound like this is no small feat. It’s a great achievement, particularly given the exciting properties of the compound, which give it potential for use in the treatment, prevention and transmission-blocking of malaria."
- Dr Paul Willis, Director, Drug Discovery, Medicines for Malaria Venture
Our TB lead optimisation team works to identify pre-clinical drug candidates with joint support from the Bill & Melinda Gates Foundation and the Wellcome Trust. As part of the international TB Drug Accelerator program, we collaborate closely with international TB biology experts and pharmaceutical companies including GlaxoSmithKline (GSK), Eli Lilly and AbbVie.
The DDU is part of an international consortium, HIT-TB, led by the National Institute of Allergy and Infectious Diseases, USA. The consortium carries out hit discovery and early hit to leads chemistry with the aim of identifying compound series which work through novel mechanisms, have suitable properties for demonstration of efficacy in pre-clinical models of TB and are ready for lead optimisation.
"We work closely with the DDU both within the TB Drug Accelerator Consortium and through our partnership with DNDi. The DDU scientists are highly professional and collaborative, actively working closely with industry partners to identify and deliver high quality lead series which address target product profiles."
- Dr Dale J. Kempf, Distinguished Research Fellow, AbbVie, USA
We collaborate with GSK’s Kinetoplastids Discovery Performance Unit (Tres Cantos, Spain) to develop new, much needed medicines for kinetoplastid diseases. This Wellcome Trust-funded collaboration (£8.6M over 5 years) is further supported by contributions from GSK.
Visceral leishmaniasis: In a major advance on previous methodologies, we developed a new high content screening assay to identify compounds that kill Leishmania parasites growing in a human macrophage-like cell line and used it to identify several promising compound series. When administered orally in a rodent disease model, compounds from one of these exhibit activity comparable to that of clinically-used drugs. We are now working with GSK to select a pre-clinical candidate from this series. In addition we have, in collaboration with Professor Alan Fairlamb (UoD), identified fexinidazole as suitable for Phase II clinical trials for visceral leishmaniasis in Africa as part of the Drugs for Neglected Diseases initiative.
Chagas’ disease: We have developed two new assays: the first is a high content screening assay for compounds which kill Trypanosoma cruzi parasites growing in mammalian cells, while the second is a robust follow-up assay to exclude hits that work through a mode of action which is commonly identified but has been shown not to work in the clinic. This new compound triaging method has identified two orally bioavailable lead series whose activity in a mouse disease model is comparable with that of clinically used drugs; one of these has now entered lead optimisation at GSK.
"Working with the Drug Discovery Unit has provided a powerful partnership to develop potential new therapies for kinetoplastid diseases. The Unit has demonstrated a highly profession attitude across all disciplines, delivering against shared goals and objectives, and is responsive to the requirements of GSK and downstream development partners."
- Dr Jose Fiandor-Roman, Head of Kinetoplastid DPU, GlaxoSmithKline, Diseases of the Developing World, Tres Cantos, Spain
Human African trypanosomiasis: We have validated the enzyme N-myristoyltransferase as a novel drug target for HAT (also known as African sleeping sickness) and developed potential pre-clinical candidates for stage 1 disease, as reported in Nature. Further compounds from the programme are being developed as treatments for African animal trypanosomiasis in partnership with GALVmed, a not-for-profit global alliance of public, private and government partners.
"It has been a very productive research collaboration with the University of Dundee DDU group. In my interactions they have demonstrated committed and professional expertise in chemistry covering a wide range of research activities from discovery chemistry analog design and synthesis, running in vivo efficacy models and DMPK studies to support new animal trypanocide drug discovery. They are a responsive, resourceful and dedicated team of experts who are assisting greatly in discovering and advancing suitable leads in this important area."
- Grant Napier, Animal African Trypanosomiasis Programme Manager, GALVmed, Edinburgh, UK