1. Helen Price and Paul Horrocks APPMG, September 2014

2. Delivering Health Research with a focus on insect- borne tropical diseases Delivering Economic Impact Influencing Policy Communicating Research UK / International Collaborations

3. 11 Research Groups (3 Professors, 4 Early Career) Haldane Multi-User Laboratory Field sites. Including Mali and Brazil Insectaries Aquarium Cat3 cell culture Gas/liquid separation and spectrometry Proteomics X-ray crystalography Imaging Radioactive room Olfactory behaviour

4. VectorParasite Host CAEP - Health Research with a focus on insect-borne tropical diseases The blood-brain-barrier Adhesion to vascular endothelium Transgenic mosquitoes refractory to infection Mosquito fitness and population structure Mosquito olfaction Chemical communication in sandflies Genetic/epigenetics in gene expression Comparative genomics Invasion blocking with sulphated carbohydrates Antimalarial screening and assay development Antileishmanial drug development

5. Antimalarial drug development – screening out the “fast-acting” drugs Paul Horrocks APPMG, September 2014

6. The challenge…… Small molecule drugs are a critical component of any malaria control policy Currently met using Artemisinin combination therapies. Artemisinins are potent and rapid acting. Artemisinin treatment failure/evolving resistance Demand that we search for novel chemotypes

7. DiscoveryPreclinicalClinicalApproval Drug > 2 million compounds 15000 in TCAMs set 400 in “Malaria Box” Our aim is to help streamline the development process by introducing in vitro assays for pharmacodynamic action in the preclinical stage We hope to impact on time-to- clinic and improve cost efficiency of the drug development process

8. Antimalarial drugs: a bioluminescence assay to rapidly estimate rate-of-kill Sensitive and rapid assay format Excellent signal/noise ratio, minimal background signal Simple to develop reproducible data Scalable for high throughput screens P. falciparum parasite GM parasite – expresses luciferase Bioluminescence Add luciferin No drug + drug

9. Screening the MMV “Malaria Box” lead drug candidates Increasing rate of kill Pre-screening eliminated 100 drugs from the assay as showing no activity within 6hrs of start of treatment

10. Fast-acting drugs in the MMV “Malaria Box” Target Candidate profile 1:‘Fast clearance’, reducing the initial parasite burden “…the expectation is that molecules will have a parasite reduction rate…at least as fast as 4-aminoquinolines, and ideally faster than artemisinin derivatives.” 14 ideal candidates 26 at least as fast as 4AQ.

11. Future work What common (novel) structural features do fast acting drugs share? Adapt the assay to act as a community research tool to provide support for the design of novel antimalarial drugs

12. New therapeutics for kinetoplastid diseases Helen Price APPMG, September 2014

13. Leishmaniasis and Sleeping Sickness: the challenge Regions of extreme poverty, poor healthcare, conflict Animal hosts act as ‘reservoirs’ Old toxic drugs Drug resistance No vaccines

14. Regions of extreme poverty, poor healthcare, conflict Animal hosts act as ‘reservoirs’ Old toxic drugs Drug resistance No vaccines Original samples of Suramin (Bayer 205) developed in 1916 Leishmaniasis and Sleeping Sickness: the challenge

15. Challenges for Kinetoplastid Drug Development Trypanosoma brucei Cross blood-brain barrier in late-stage disease Leishmania Inside host macrophages Acidic environment 3 membranes to cross Parasites pump drugs out

16. Drug Development Strategies 1. Phenotype-based approach + X ? Parasite Test compound Parasite death 2. Targeted-based approach An essential protein in the parasite + Test compound Inhibits the role of the protein X ? X ? Parasite death

17. NMT Inhibitors as Potential Drugs (1) NMT Enzyme Known drug target in fungal pathogens Essential for survival of T. brucei and L. donovani + Test compound High-throughput screens: 100,000 compounds - T. brucei NMT (Drug Discovery Unit, Dundee) 150,000 compounds - L. donovani and P. falciparum NMT (Pfizer)

18. NMT Inhibitors as Potential Drugs (2) T. brucei Potent NMT inhibitors kill parasites in vitro and in mouse model Unable to cross blood-brain barrier Repositioning as veterinary drug and anti-cancer therapy (DDU) L. donovani NMT inhibitors very effective on protein but less potent on parasite

19. Focus on Cutaneous Leishmaniasis (CL) Cutaneous, mucocutaneous and visceral forms Cutaneous disease: over 75% of all cases Toxic drugs versus no treatment Drug discovery programmes for species causing visceral disease Cutaneous Mucocutaneous Visceral

20. Magnetic nanoparticles to treat CL? Collaboration with Neil Telling and Clare Hoskins at Keele Chemical coatings to target nanoparticles to correct cells Can control heat by strength of magnetic field Use on multidrug-resistant parasites May also kill bacterial pathogens Portability is an issue: development of magnetic bandages and devices at Keele

21. Acknowledgements: Research colleagues at CAEP Prof. Debbie Smith of University of York The following organisations for funding and access to small molecules: Helen Price: h.price@keele.ac.uk, Twitter: @helenpprice Paul Horrocks: p.d.horrocks@keele.ac.uk