helen price and paul horrocks appmg, september 2014
TRANSCRIPT
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Helen Price and Paul Horrocks
APPMG, September 2014
![Page 2: Helen Price and Paul Horrocks APPMG, September 2014](https://reader030.vdocuments.net/reader030/viewer/2022032702/56649ce25503460f949ad759/html5/thumbnails/2.jpg)
• Delivering Health Research with a focus on insect-borne tropical diseases
• Delivering Economic Impact
• Influencing Policy
• Communicating Research
• UK / International Collaborations
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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
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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
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Antimalarial drug development – screening out the “fast-acting” drugs
Paul Horrocks
APPMG, September 2014
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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
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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
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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
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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
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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.
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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
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New therapeutics for kinetoplastid diseases
Helen Price
APPMG, September 2014
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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
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• 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
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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
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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
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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)
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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
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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
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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
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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]