Transcript Price Horrocks 02-09-14

Helen Price and Paul Horrocks
APPMG, September 2014
• Delivering Health Research with a focus on insectborne tropical diseases
• Delivering Economic Impact
• Influencing Policy
• Communicating Research
• UK / International Collaborations
11 Research Groups
(3 Professors, 4 Early Career)
Insectaries
Aquarium
Cat3 cell culture
Haldane Multi-User
Laboratory
Gas/liquid separation and
spectrometry
Proteomics
X-ray crystalography
Imaging
Radioactive room
Olfactory behaviour
Field sites.
Including Mali and Brazil
CAEP - Health Research with a focus on
insect-borne tropical diseases
Vector
Parasite
Genetic/epigenetics in
gene expression
Transgenic mosquitoes
refractory to infection
Comparative genomics
Mosquito fitness and
population structure
Invasion blocking with
sulphated
carbohydrates
Mosquito olfaction
Host
Chemical
communication in
sandflies
Antimalarial screening
and assay
development
Antileishmanial drug
development
The blood-brain-barrier
Adhesion to vascular endothelium
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
400 in
“Malaria Box”
Preclinical
15000 in TCAMs set
> 2 million compounds
Discovery
Clinical
Approval
Drug
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-toclinic and improve cost
efficiency of the drug
development process
Antimalarial drugs: a bioluminescence assay to rapidly
estimate rate-of-kill
P. falciparum parasite
GM parasite –
expresses luciferase
No drug
+ drug
P. falciparum parasite
Add luciferin
Add luciferin
Bioluminescence
• Sensitive and rapid assay
format
• Excellent signal/noise ratio,
minimal background signal
• Simple to develop
reproducible data
• Scalable for high throughput
screens
Screening the MMV “Malaria Box” lead drug candidates
Pre-screening eliminated 100 drugs from
the assay as showing no activity within
6hrs of start of treatment
Increasing rate of kill
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
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
Original samples of Suramin (Bayer
205) developed in 1916
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
X
+
An essential protein
in the parasite
Test compound
?
?
Inhibits the role
of the protein
X
Parasite death
?
NMT Inhibitors as Potential Drugs (1)
• Known drug target in fungal pathogens
• Essential for survival of T. brucei and L. donovani
NMT Enzyme
High-throughput screens:
• 100,000 compounds - T. brucei NMT
+
Test compound
(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]