Helen Price and Paul Horrocks APPMG, September 2014.
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Transcript of Helen Price and Paul Horrocks APPMG, September 2014.
Helen Price and Paul Horrocks
APPMG, September 2014
• Delivering Health Research with a focus on insect-borne tropical diseases
• Delivering Economic Impact
• Influencing Policy
• Communicating Research
• UK / International Collaborations
11 Research Groups (3 Professors, 4 Early Career)
Haldane Multi-User Laboratory
Field sites. Including Mali and Brazil
InsectariesAquariumCat3 cell culture
Gas/liquid separation and spectrometryProteomicsX-ray crystalographyImagingRadioactive roomOlfactory behaviour
Vector Parasite
Host
CAEP - Health Research with a focus on insect-borne tropical diseases
The blood-brain-barrierAdhesion 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
Antimalarial drug development – screening out the “fast-acting” drugs
Paul Horrocks
APPMG, September 2014
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
Discovery Preclinical Clinical Approval
Drug
> 2
mill
ion
com
poun
ds
1500
0 in
TCA
Ms
set
400
in
“
Mal
aria
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
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
P. falciparum parasite
GM parasite – expresses luciferase
Bioluminescence Bioluminescence
Add luciferinAdd luciferin
No drug + drug
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
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.
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
New therapeutics for kinetoplastid diseases
Helen Price
APPMG, September 2014
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
• 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
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
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
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)
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
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
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
Acknowledgements:
Research colleagues at CAEP
Prof. Debbie Smith of University of York
The following organisations for funding and access to small molecules:
Helen Price: [email protected], Twitter: @helenpprice
Paul Horrocks: [email protected]