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: h.price@keele.ac.uk, Twitter: @helenpprice

Paul Horrocks: p.d.horrocks@keele.ac.uk