EsKITIs INsTITUTE
DRUG DIsCOVERY REsEARCH
“The Eskitis Institute is at the forefront of discovering new
treatments for a wide range of critical diseases.”
Professor Ian O’Connor, Vice Chancellor and President, Griffith University
griffith.edu.au/eskitis
The Eskitis Institute - Multidisciplinary Drug Discovery
Our Research
Unique resources and capabilities
Griffith University provides a setting of international standard
for the pursuit of learning, teaching, research and professional
practice. Griffith is ranked in the top 5% of universities worldwide.
Eskitis is located in two buildings, Eskitis 1 & 2, located on the
outskirts of Griffith University’s Nathan Campus. Our research is
supported by unique in-house capabilities, including the following:
The Eskitis Institute is a flagship research centre of Griffith
Universitythat focuses on drug discovery research. Eskitis offers
an excellent environment for drug discovery research in areas
such as:
Nature Bank is a unique drug discovery platform based on natural
products from Australia, China, Malaysia and Papua New Guinea.
This biodiversity resource comprises >45 000 samples of plants
and marine invertebrates, >18 000 extracts, >200 000 semipurified fractions and >3 250 pure compounds. Nature Bank is
an ideal resource for drug discovery research and is being actively
used by projects in partnership with academic and industry groups.
•
Cancer (including prostate, pancreatic and breast cancer)
Neurodegenerative diseases (including Parkinson’s
disease, schizophrenia and Alzheimer’s disease)
Infectious diseases (including emerging antibioticresistant infections)
Global Health (including malaria, African sleeping sickness,
tuberculosis and HIV)
Eskitis researchers collaborate widely, with research partners on
every continent, and hosts researchers and students from across
the world.
study with us
The Eskitis Institute offers many opportunities for Masters
and PhD study in drug discovery projects. Eskitis is a truly
multidiscplinary research and training environment with an equal
proportion of chemistry and biology researchers.
Potential PhD study areas include:
Medicinal chemistry
Natural product chemistry (including marine invertebrates,
plants and microorganisms)
Traditional Chinese Medicines
synthetic chemistry
Bioaffinity Ms screening
Neurobiology
Cancer tumour biology
Adult stem cell biology
Parasitology
(visit nature-bank.com.au for more)
Neuro Bank is a collection of well-characterised human
olfactory neurosphere-derived (hONs) cells from over 200
neurology patients. Neuro Bank represents excellent models of
neurological diseases to support research on Parkinson’s disease,
schizophrenia and other diseases.
Queensland Compound Library is an automated library of over
330 000 pure compounds from Australian chemists. The QCL
is a national facility conceived to facilitate and drive interactions
between chemists and biologists in Australia or overseas.
(visit griffith.edu.au/qcl for more)
Drug Discovery capabilities include a core of industry-standard
drug discovery infrastructure including High Throuhgput
screening. High throughput imaging is enabled by high content
confocal screening systems, allowing the examination of the
effect of compounds on individual cells.
Mass Spectrometry facilities include 4.7 and 12 Tesla Fourier
transform ion cyclotron resonance mass spectrometers (FTMs)
for high resolution protein analysis. These instruments allow
real-time observation and isolation of protein complexes.
Nuclear Magnetic Resonance facilites include 500 and 600
Mhz units, allowing high resolution spectroscopy to quickly solve
the structure of small molecules
“The innovative work being conducted at the
Eskitis Institute can accelerate and revolutionise
our approach to fighting disease.”
- Professor Ronald J Quinn AM, Eskitis Institute Director
Andrews Group Research
Human parasitic diseases cause major health and economic
problems in many tropical and sub-tropical regions of the
world. Each year significant morbidity and mortality arises due
infection with parasites that cause diseases such as malaria,
schistosomiasis, and lymphatic filariasis. There are currently
no vaccines available to prevent tropical parasitic diseases and
prophylactic or therapeutic drugs are either failing due to parasite
resistance or are just not available. Our work focuses on the
worlds’ most lethal tropical parasitic disease, malaria, which is
caused by Plasmodium parasites. Each year ~800,000 people,
mainly children under the age of five, die of malaria. Parasite drug
resistance is a major problem and there is a large unmet need
for the identification of new antimalarial drugs and novel drug
targets within the parasite. To address this, we are using targeted
medicinal chemistry approaches combined with the investigation
of key molecular and biochemical pathways in the parasite.
Andrews Group Projects
Project 1: Investigating malaria parasite histone deacetylase to
find new antimalarials
Enzymes involved in modifying proteins and regulating their
function, such as lysine deacetylases, are emerging as promising
therapeutic targets due to their importance in parasite growth and
survival. The enzymes that modify protein lysine acetylation are
called histone acetyltransferase (HATs) and histone deacetylase
(HDACs). HDACs in particular are well-validated drug targets for
many diseases (e.g. cancer), and are promising new antimalarial
drug targets. In eukaryotic cells, HDACs act on both histone and
non-histone proteins, meaning they play multiple roles including
regulation of transcription in the nucleus and other essential roles
that occur in the cytoplasm. Malaria parasite HDACs have been
found to be important for transcriptional control, but their role on
non-histone proteins and pathways are not yet known.
This is an important gap in our current understanding of how
malaria parasites grow and develop. In this project we will address
this gap by determining the role of malaria parasite HDACs on nonhistone proteins so that we can better develop new antimalarial
drugs. Given the problem of antimalarial drug resistance,
the potential to target a class of enzymes critical to multiple
essential regulatory pathways This project will employ advanced
molecular and biochemical approaches including protein:protein
interaction studies, protein expression/purification, enzyme
assays, IFA, immunoprecipitation, hyperacetylation assays, and
proteome wide acetylation studies. The project will also involve
in vitro culture of malaria parasites and standard drug discovery
approaches (e.g., growth inhibition assays and functional assays).
Project 2: Generation and characterisation of histone deacetylase
inhibitor-tolerant malaria parasites
In this project an exciting class of new antimalarial compounds will
be investigated – histone deacetylase (HDAC) inhibitors. These
compounds have promising in vitro antimalarial activity profiles,
with low nM killing activity against P. falciparum parasites and
more selective killing of P. falciparum parasites versus killing of
human cells.
Despite these findings, we know little about how these compounds
act in vivo on malaria parasites or the likelihood of resistance to
this class of compounds developing. In vitro selection of tolerant
or resistant lines is routinely employed to investigate how likely
resistance is to develop and if there is any cross-resistance
with potential partner drugs. Resistant laboratory lines are also
a very useful tool in the search for next generation antimalarial
compounds in targeted screening programs.
The aims of this project are:
To select P. falciparum parasites for in vitro resistance/
tolerance to HDAC inhibitors
To examine the phenotype of HDAC inhibitor tolerant/
resistant parasites.
In vitro HDAC inhibitor resistance/tolerance in P. falciparum lines
will be induced by exposing drug sensitive parasites to increasing,
sub-lethal, amounts of compounds or short pulses of lethal
levels of compound. Resistance/tolerance (and cross resistance
to clinically antimalarials such as chloroquine and mefloquine)
will be assessed using standard in vitro growth inhibition assays.
Molecular alterations such as point mutations in P. falciparum
HDAC genes, mutations or amplifications in other drug resistanceassociated genes, and alterations to reactive oxygen species
(ROs) will be examined.
Project 3: Mode of action studies on novel antimalarial
compounds
We recently screened a unique CsIRO library for compounds
with growth inhibitory activity against P. falciparum infected
erythrocytes. A number of novel compound classes with potent
and selective antimalarial activity were identified. The aim of this
project will be to further investigate the antimalarial potential
of some of these compounds using a range of molecular and
biological approaches.
The aims of this project are:
To investigate the in vitro pharmacodynamics and mode of
action of lead antimalarial compounds.
To screen synthesized analogues of antimalarial compounds for
structure activity relationship studies and lead-optimization.
To validate the potential of lead compounds by carrying out
basic pre-clinical evaluation studies in vivo in mouse models
of malaria.
EsKITIs INsTITUTE
DRUG DIsCOVERY REsEARCH
‘In the face of increasing antimalarial drug
resistance, it is important that we continue to
develop new ways to therapeutically target
malaria parasites. Our group uses crossdisciplinary approaches to try to identify key
weaknesses in the malaria parasite so that we can
develop new drugs to exploit these weaknesses.’
Dr Kathy Andrews, Eskitis Institute
ResearcherID URL: www.researcherid.com/rid/F-9586-2011
Contact
The Eskitis Institute
Griffith University
Tel: +61 (07) 3 735 6000 Fax: +61 (07) 373 56001
[email protected], [email protected]
griffith.edu.au/eskitis@eskitis (twitter)
Location
The Eskitis Institute
Eskitis 2 Building (N75)
Griffith University
Brisbane Innovation Park, Don Young Road
Nathan Qld 4111
Australia
Griffith University
CRICOS Provider Number 00233E
Front cover images (Clockwise from top left): Professor Ronald J Quinn AM, the Eskitis 2
Building, Professor Ian O’Connor, interior of QCL robot, eucalyptus leaves