Nwaka, S. & Hudson, A. Innovative lead discovery strategies for tropical diseases. Nat. Rev. Drug Discov. 5, 941-955

Abstract

Lead discovery is currently a key bottleneck in the pipeline for much-needed novel drugs for tropical diseases such as malaria, tuberculosis, African sleeping sickness, leishmaniasis and Chagas disease. Here, we discuss the different approaches to lead discovery for tropical diseases and emphasize a coordination strategy that involves highly integrated partnerships and networks between scientists in academic institutions and industry in both wealthy industrialized countries and disease-endemic countries. This strategy offers the promise of reducing the inherently high attrition rate of the early stages of discovery research, thereby increasing the chances of success and enhancing cost-effectiveness.

Full text

There is a continuing and compelling need for new and
improved treatments for developing-world diseases.
These include bacterial, protozoan and helminth infec-
tious diseases such as tuberculosis, malaria, African
sleeping sickness, leishmaniasis, Chagas disease,
onchocerciasis, lymphatic filariasis and schistosomiasis
1–3
.
A number of factors limit the utility of existing drugs
in resource-poor settings, such as high cost, poor com-
pliance, drug resistance, low efficacy and poor safety
2
.
Because the evolution of drug resistance is likely to com-
promise every drug in time, the demand for new thera-
pies is continuous. Accordingly, a vibrant drug discovery
pipeline is needed to help to ensure the availability of
new products that will reduce mortality and morbidity
resulting from these infections
4,5
.
Discovering lead compounds with the potential
to become usable drugs is a crucial step to ensuring a
sustainable global pipeline for innovative products
4,6
. In
recognition of this need a number of agencies, includ-
ing the Special Programme for Research and Training
in Tropical Diseases at the World Health Organization
(WHO/TDR), various international/national bodies
and philanthropic foundations, have been supporting
the discovery of such agents for tropical diseases (see
Further information for organizations likely to support
this type of research). Some of the fruits of these programmes
have already been taken forward by public–private
partnerships (PPPs)
5,7,8
.
Drug development PPPs that focus on product
identification for specific tropical diseases often require
quality lead compounds to feed into their preclinical pipe-
lines. Some of these organizations are making significant
progress in trying to bring products to the market
through enhanced development programmes, but place
less emphasis on the risky early phases of the discovery
process
2,9,10
. However, owing to the paucity of robust
lead series, these organizations are now trying to invest
more in the early stages of drug discovery. For example,
the Medicines for Malaria Venture (MMV) has recently
initiated a focused call for drug discovery projects to
boost its antimalarial pipeline. In addition, a number
of the diseases mentioned above (lymphatic filariasis,
onchocerciasis and schistosomiasis) lack dedicated
PPPs for innovative product discovery and development.
Recent reports have highlighted the gaps, needs and
opportunities for increased investment and activity in
translational research for new product leads
10–12
. It should
be noted that lead discovery tends not to receive much
funding from the normal scientific granting bodies,
and so there is less incentive for academia to work in
this area.
The majority of international R&D funding and aid
for infectious diseases affecting the developing world is
focused on the ‘big three’ healthcare problems — HIV,
tuberculosis and malaria
9,13
. This is understandable
given the high burden of these diseases. However, there
is a compelling need to invest in innovative strategies to
address the other largely neglected infectious diseases
prevalent in the developing world via enhanced transla-
tional research for new products, as well as capacity build-
ing and utilization in disease-endemic countries
11,14,15
.
We lack a robust pipeline of products in discovery and
development to deliver drugs that meet the desired target
product profiles
(TABLE 1) for these diseases
2,5,16,17
.
Special Programme for
Research and Training in
Tropical Diseases (TDR),
World Health Organization
Geneva, Switzerland.
Correspondence to S.N.
e-mail: nwakas@who.int
doi:10.1038/nrd2144
Published online
13 October 2006
Innovative lead discovery strategies
for tropical diseases
Solomon Nwaka and Alan Hudson
Abstract | Lead discovery is currently a key bottleneck in the pipeline for much-needed
novel drugs for tropical diseases such as malaria, tuberculosis, African sleeping sickness,
leishmaniasis and Chagas disease. Here, we discuss the different approaches to lead
discovery for tropical diseases and emphasize a coordination strategy that involves highly
integrated partnerships and networks between scientists in academic institutions and
industry in both wealthy industrialized countries and disease-endemic countries.
This strategy offers the promise of reducing the inherently high attrition rate of the early
stages of discovery research, thereby increasing the chances of success and enhancing
cost-effectiveness.
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So, there is an urgent requirement for a coordinated
approach involving multi-disciplinary networks of
investigators, as well as partnerships between industry
and the public sector in both developed and developing
countries. One such approach that considers networks,
partnerships and capacity building in an integrated lead
discovery process is illustrated in
FIG. 1. The present paper
discusses strategies to meet the need for lead compounds
for further development for tropical diseases. Specific
examples are drawn from the work of the WHO/TDR
covering a broad range of tropical diseases and from the
approaches taken by other agencies in these areas.
Strategies for drug discovery
The discovery of novel therapeutics for tropical diseases
has largely relied on three strategies: label extension,
piggy-back discovery and de novo drug discovery.
Label extension. Until recently, the primary strategy
for drug discovery for tropical diseases was based
on extending the indications of existing treatments
for other human and animal ailments to tropical
diseases
5,18,19
. This fast-track approach has been suc-
cessful and has resulted in some of the most important
antiparasitic drugs in use today, such as ivermectin
for filariasis/onchcocerciasis, and praziquantel for
schistosomiasis
20–23
(TABLE 2). It continues to have a
major role in the global drug discovery and develop-
ment strategy for tropical diseases. For example, the
veterinary anthelminthic product moxidectin, an
analogue of ivermectin
24
, is being taken into Phase II
clinical trials for the treatment of lymphatic filaria-
sis and onchocerciasis. The main attractions of this
approach are the reductions in cost and time to market
that can be achieved. In addition, over the past three
decades there have been few specific drug discovery
programmes supported by the pharmaceutical industry
that target tropical diseases. However, concern related
to over-reliance on label extensions has arisen in recent
years: many companies have been reluctant to allow
their products to be developed for tropical diseases in
case their economic potential is blighted by unexpected
Table 1a | Limitations of available drugs for parasitic diseases and proposed target profile for new drugs
Some available drugs and their limitations* Proposed target profile
Malaria
• Quinine (1930): compliance, safety, resistance
• Chloroquine (1945): resistance
• Primaquine (1948): safety
• Sulfadoxine/pyrimethamine (1961):
resistance
• Mefloquine (1984): resistance, safety
• Artemisinins (1994): compliance, cost, Good
Manufacturing Practice
• Atovaquone/proguanil (1999): cost
For uncomplicated falciparum malaria
• Orally active
• Low cost of goods (~US$1 per full course treatment)
• Effective against drug-resistant parasites; low propensity to generate rapid resistance
• Curative within 3 days
• Fast acting
• Potential for combination with other agents
• Paediatric formulation
• Stable under tropical conditions (shelf life of >2 years)
Further profiles
• Intermittent treatment in pregnancy and early infancy
• Plasmodium vivax malaria
• Severe malaria
• Prophylaxis
• Single dose cure
Leishmaniasis
• Pentamidine (1939): safety and efficacy/
resistance issues, injectable
• Antimonials (1950): safety and efficacy/
resistance issues, injectable
• Liposomal Amphotericin B (1990):
cost, injectable
• Miltefosine (2002): contraindicated in
pregnancy
• Active against all visceral and cutaneous leishmaniasis
• Short course of treatment (≤14 days)
• Single daily dose, but alternate days or weekly dosing acceptable
• Injectable with reduced treatment time acceptable
• Oral drug desired
• Safer than available treatment
• Safe in children and pregnancy desired
• Cost less than current treatments (US$200–400)
• Stable under standard tropical conditions (shelf life >2 years)
Further profiles
• Topical application for cutaneous leishmaniasis desired
• Potential for combination with existing agents
Human African trypanosomiasis
• Suramin (1920): safety, not effective in late-
stage disease, injectable
• Pentamidine (1939): safety and resistance
issues, injectable, not effective in late-
stage disease
• Melarsoprol (1949): safety and resistance
issues, injectable
• Eflornithine (1991): cost, injectable, only
effective in Trypanosoma gambiense
• Active against both major species Trypanosoma rhodesiense and T. gambiense
• Active against known resistance strains for example, melarsoprol failures
• Treatment for early-stage diseases acceptable but efficacy against both early- and late-stage desired
• Parenteral administration for late-stage disease
• Oral formulation for early-stage disease desired
• Cure in 14 days or less
• Cost less than current treatment for early stage disease ($100–140)
• Safe in pregnancy
• Stable under tropical conditions (shelf life >2 years)
*The dates in parentheses are the approximate dates when the drugs were first used (information adapted and modified from REFS 2,5,22).
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toxicities in these patient classes
5
. This, and other factors,
has driven the quest for novel products for tropical
diseases using additional discovery strategies
5,25
.
‘Piggy-back’ discovery. The ‘piggy-back’ strategy is most
useful when a molecular target present in parasites is
being pursued for other (commercial) indications as it
facilitates the identification of chemical starting points
26
.
Specific examples of this approach include the antimalarial
screening of lead series of histone deacetylase inhibitors
27
that were originally developed for cancer chemotherapy,
and cysteine protease inhibitors that are being developed
for osteoporosis
18
. It should be noted that structure–
activity relationships emerging from the parasite assays
are unlikely to be the same as those observed for the
original indication. It is therefore likely that optimized
clinical candidates emerging from this strategy will be
disease-specific.
De novo drug discovery. This strategy focuses on the iden-
tification of new chemical entities, both synthetic com-
pounds and natural products, as novel antiparasitic drugs.
It is more long-term than the approach discussed above
and integrates discovery research based on target-based
high-throughput screening (HTS) and medium through-
put screening (MTS) in whole-parasite assays against
specific proteins and whole parasites.
Target-based HTS campaigns have been emphasized
in recent years as a way of harvesting the significant
investment made in parasite genomics programmes by
the international community
28–31
. However, difficul-
ties encountered in moving resultant hits through the
pipeline — for example, in demonstrating a correlation
between enzyme inhibition and activity against whole
parasites — has generated interest in developing HTS
techniques for whole-organism screening
25,32–35
. Recent
whole-cell-based HTS campaigns using compound
libraries containing registered drugs have yielded encour-
aging results
34,35
. In addition, chemoinformatic meth-
odologies linked to genomics, in silico screening
36–38
,
as well as the structural determination of proteins and
their co-crystallization with small molecules, are now
being applied for antibacterial and antiparasitic drug
discovery
39–42
.
MTS in whole-parasite assays using compounds cho-
sen on the basis of a biological, biochemical or structural
rationale remains the most pursued screening option
for parasitic diseases
5,25,43
. The main disadvantage of
Table 1b | Limitations of available drugs for parasitic diseases and proposed target profile for new drugs
Some available drugs and their limitations* Proposed target profile
Chagas disease (American trypanosomiasis)
• Nifurtimox (1970): safety, long treatment
compliance, activity limited to acute stage of
disease
• Benznidazole (1974): safety, activity limited to
acute stage of disease
• Active against blood and tissue forms of disease
• Active in chronic forms of the disease
• Parental administration with reduced treatment time acceptable
• Oral drug desired
• Improved safety over current products (free of cardiac effects)
• Paediatric formulation
• Safe for use in children and pregnancy
• Inexpensive
• Stable under tropical conditions (shelf life >2 years)
Schistosomiasis
• Oxamniquine (1967): only effective against
Schistosoma mansoni, multiple dosing, cost
• Praziquantel (1975): does not kill young
worms and eggs; possible resistance reported
• New chemical class; alternative to praziquantel is important in the context of resistance
development
• New mechanism of action: drug active against mature and immature forms of parasites
including eggs
• Active against all major types of schistosome infections
• Safety equal or better than praziquantel
• Oral use
• Inexpensive
• Short treatment courses (ideally single oral dose)
• Safety profile compatible with use without diagnosis
• Safe in children, pregnant women desired
• Stable under tropical conditions (shelf life >2 years)
Lymphatic filariasis and onchocerciasis
• Diethylcarbamazine (1949): safety, not a
macrofilaricide, not used in Onchocerca
volvulus endemic areas
• Albendazole: only used in combination
therapy, little acute microfilaricidal effect
• Ivermectin (1989): not a macrofilaricide,
regular administration needed to kill young
worms
• New chemical class: alternative to ivermectin and albendazole, important in the context of
resistance development
• Macrofilaricidal or permanent sterilization of adult worms (in addition to being microfilaricidal)
• Slow action (avoid rapid death of worms to prevent side effects due to immune responses)
• Oral use
• Inexpensive
• Safety equal or better than ivermectin or combinations for LF
• Short treatment courses (ideally single oral dose)
• Safety profile compatible with use without diagnosis
• Safe in children, pregnant women
• Stable under tropical conditions (shelf life >2 years)
*The dates in parentheses are the approximate dates when the drugs were first used (information adapted and modified from REFS 2,5,22).
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M
e
n
t
o
r
s
h
i
p
I
n
d
u
s
t
r
y
In vitro/vivo
screening
network
Capacity
buiding/
fellowships
Quality
leads
Optimization
Interface with other players
Drug
candidates
Pharmacokinetics/
metabolism network
Medicinal
chemistry
network
Validated
drug targets
HTS
Target
Portfolio
Network
Compounds
(known rationale,
diverse, natural
products)
Hits
Hits
Leads
A
c
a
d
e
m
i
a
this approach is the low throughput of available assays
(especially those using filariae and schistosomes), and
the limited investment in the development of new robust
assays. A recurring difficulty for all screens (HTS or
MTS) for neglected diseases is the availability of high-
quality compound libraries. Efforts are now being made
to establish compound libraries and HTS screening
capacity at public institutions
(TABLE 3).
It should be mentioned that so far in the field of
anti-infective (including antiparasitic) drug discovery,
the target-based HTS approach has yielded few success
stories
6,44–46
. In part this reflects the high rate of attrition
in the process of progression from early-stage biochemi-
cal hits to robust lead compounds. Many compounds
active in protein-based assays are inactive in whole cells.
This can be due to failure to enter intact cells but can
also occur because the chosen molecular targets are not
in fact essential to the microbes. The latter issue sug-
gests that more work on target validation is needed to
increase confidence levels in the selection of protein
candidates for HTS campaigns. The initial challenge of
identifying molecular targets that are crucial to parasite
survival, coupled with the identification of whole-cell
active compounds, is formidable — and this challenge
is made harder by the need to achieve efficacy in small
animal disease models combining an appropriate level
of potency with suitable pharmacokinetics. With the
possible exception of the cysteine protease inhibitor
K777, which is in development for Chagas disease
47
, the
authors are not aware of any compound in late discovery
phase or development for a human protozoan or
helminth disease that has resulted from a target-based
HTS campaign. The strategy is still valid but needs to be
augmented by increased efforts to select and focus on
validated molecular targets and to improve the quality of
compound libraries selected for the initial screening exer-
cise. It should be seen as complementary to whole-cell
screening and not as a substitute for it.
Figure 1 | An innovative lead discovery strategy for tropical diseases. This strategy involves networks and
partnerships with industry and academic institutions worldwide to deliver specific drug discovery objectives.
The portfolio of prioritized and validated molecular targets developed by the target portfolio network will be used
in high-throughput screening (HTS) efforts at various institutions (academia and industry). Hits* emerging from the
screening are assessed in whole parasites (in vitro) through the compound-evaluation network. In addition, compounds
with an established biological/biochemical rationale or diverse structures, as well as natural products, are sourced and
channelled into the compound-evaluation network for whole-parasite screening, with actives subsequently being tested
in animal disease models. Through iterative medicinal chemistry and pharmacological profiling using the appropriate
network, structure–activity relationships are developed and used to guide synthesis of analogues with enhanced activity.
The resulting drug-like lead compounds will then be progressed into focused optimization programmes in collaboration
with other partners. The integrated lead discovery strategy of the Special Programme for Research and Training in Tropical
Diseases at the World Health Organization (WHO/TDR) involves experienced consultants or mentors who support and
provide guidance on various aspects of the preclinical process and to the postdoctoral fellows from disease-endemic
countries who are working and being trained on the programme. The involvement of institutions worldwide in the various
network activities calls for increased management and fruitful capacity building, especially in the disease-endemic
countries. Interactions between the different networks and quality control are managed by WHO/TDR. In this respect,
a central database housed at WHO/TDR is a crucial resource for managing individual projects and processing data and
compounds. *A ‘hit’ is compound with selective in vitro activity (usually IC
50
<1μM) against the target whole organism
and/or protein; a ‘lead’ is a compound with druggable characteristics, that is efficacious in disease animal models with no
overt toxicity; a ‘drug candidate’ is an optimized lead compound with in vitro and in vivo activity equivalent or better than
drug standards, acceptable pharmacokinetic and toxicity profile, with a synthesis that is amenable to cost-effective
scale-up. Activity criteria for ‘hit’ and ‘lead’ compounds are presented in
BOX 1.
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The tripartite strategy pursuing ‘label extension’, ‘piggy-
back’ and ‘de novo drug discovery’ is integrated into the
network and partnership model described below.
Network/partnership models for lead discovery
In recent years, a number of networks, partnerships and
consortia have been established specifically to pursue
tropical disease research. Important examples include
the following:
• A collaborative network of institutions supported
under the Grand Challenges in Global Health initia-
tive (funded by the Gates Foundation and Wellcome
Trust; see Further information) to address infectious
disease problems — for example, those with the goal
to discover drugs and delivery systems that limit drug
resistance for infectious diseases (see Further infor-
mation, Grand Challenges in Global Health initiative
— Limit drug resistance)
48
.
• The various European Union drug discovery initiatives,
such as the FP6, support consortia (for example, the
Antimal Drug Discovery network for malaria, which
consists of scientists from over 20 institutions, including
academia and industry; see Further information, EU
Commission — Poverty-Related Diseases) as well
as the network focusing on new drugs for persistent
tuberculosis (see Further information, EU Commission
— New TB Drugs).
• Several drug discovery projects present within the
portfolio of PPPs such as MMV, Drugs for Neglected
Diseases Inititative (DNDi) and Global Alliance for TB
Drug Development (GATB). For example, the anti -
malarial synthetic peroxide project is based on the network
paradigm
7
, as is the 8-aminoquinoline project at the
University of Mississippi, which is supported by both
MMV and DNDi for malaria and leishmaniasis.
• A consortium supported by the Gates Foundation for
the discovery of new drugs for African sleeping sick-
ness is focused on the dicationic structure scaffold
49,50
.
The team consists of investigators from the University
of North Carolina, the Swiss Tropical Institute (STI),
Ohio State University, Kenya Trypanosomiasis Research
Institute, London School of Hygiene and Tropical
Medicine (LSHTM) with Immtech International as
the industrial partner.
Another fairly recent development is the emergence of
dedicated academic and public initiatives that focus on
various aspects of drug discovery for tropical and non-
tropical diseases
2,10,51–53
. Such initiatives are largely sup-
ported with external funding and aim to approach the
level of drug discovery resources and expertise present
in small-to-medium-size biopharmaceutical companies.
Efforts of these centres include HTS and MTS using
synthetic small-molecule and natural-product libraries
(TABLE 3). Examples include the University of Dundee’s
drug discovery initiative for trypanosomiasis and
leishmaniasis, funded by the Wellcome Trust and other
agencies, which encompasses HTS screening capability,
molecular and parasite biology, and medicinal chemistry
supported by ADME (absorption, distribution, metabo-
lism and excretion) assays. Another example is the
University of California San Francisco Sandler Center
and Tropical Diseases Research Unit (supported by the
Sandler Family Foundation and the National Institute
of Allergy and Infectious Diseases (NIAID)), which is
a consortium of laboratories dedicated to the discovery
and development of new drugs for tropical diseases with
core competences in genomics and proteomics, struc-
tural biology, chemistry, cell-based screens as well as
pharmacokinetics. Other relevant organizations main-
taining antiparasite screening operations include the
Harvard/Broad initiative, the Walter Eliza Hall Institute
for Medical Research and the St Jude Children’s Research
Hospital Memphis
(TABLE 3).
The above organizations are all making valuable
contributions in one way or another in the search for
new therapies for specific tropical diseases. However,
as the goal of these initiatives is to discover new leads
or drug candidates for tropical diseases, we now need
a strategy to track and monitor the progress of these
activities and to avoid unnecessary duplication of effort.
A coordination strategy that enhances networking and
exchange of information between these entities would
help to maximize the return on the investment made by
the various stakeholders. One possible way of enhancing
information flow is to set up a website on which inves-
tigators are encouraged to record what HTS campaigns
they have conducted or which are ongoing.
The integrated and centrally coordinated strategy
discussed below represents a focused attempt by WHO/
TDR to address a specific gap in the earlier phases of
the discovery pipeline: the identification of robust lead
compounds for tropical diseases. The idea is to share
some lessons that might be helpful for institutions
Table 2 | Some available drugs for tropical diseases
Diseases Drug Origin
Chagas’ disease Benznidazole Veterinary R&D (Roche)
Nifurtimox Veterinary R&D (Bayer)
Human African
trypanosomiasis
Eflornithine (DFMO) Anticancer R&D (MMD/TDR)
Leishmaniasis Lipo. Ampho. B (NexStar/WHO)
Miltefosine Anticancer R&D (Zentaris/TDR)
Schistosomiasis Praziquantel Veterinary R&D (Pfizer/TDR)
Oxamnaquine Veterinary R&D (Pfizer)
Helminth infections Albendazole Veterinary R&D (SKB)
Onchocerciasis Ivermectin Veterinary R&D (Merck/TDR)
Malaria Mefloquine (WRAIR/H-LaRoche/TDR)
Halofantrine (WRAIR/SKB/TDR)
Artemether (China/RPR/TDR)
Atovaquone/prog. (Wellcome (now GSK))
Arteether (Artecef/TDR)
Lapdap (GSK/TDR)
Lumefantrin/Artemeter (Novartis)
Companies and partners involved in their development are indicated. The original indications
for some of the drugs are highlighted. MMD, Marion Merrell Dow; SKB, SmithKline Beecham
(now GSK, Glaxo SmithKline); RPR, Rhône-Poulenc Rorer.
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working on drug discovery for tropical diseases. For
many years, WHO/TDR has focused its drug discovery
resources on funding a network of compound assess-
ment centres
(FIG. 2). The need to follow up actives
emerging from these test centres with dedicated medic-
inal chemistry backed up by pharmacokinetic investi-
gations has now been recognized and supported with
the establishment of two further specialist networks.
Furthermore, in order to harness the output from the
various parasite genome programmes
28–30
, an additional
network has been created to triage bioinformatic data
and to identify a pipeline of molecular targets for
various disease-causing parasites. These networks are
described below.
The drug target portfolio network. In order to interpret
and capitalize on the data emerging from parasite
genome programmes, a network has been created to
develop a globally accessible database populated with a
prioritized list of potential drug targets. A comprehensive
listing of putative drug targets from human protozoan
and helminth parasites has not been carried out sys-
tematically to date. The project will help address this
issue and provide published recommendations for
selected molecular targets suitable for progression to
HTS campaigns. This should help promote the strat-
egy in both industry and academia. The TDR drug
target portfolio network consists of groups based at the
University of Washington, Seattle, USA; the University
of Pennsylvania, USA; the Sanger Centre, Cambridge,
UK; the Walter Eliza and Hall Institute for Medical
Research (WEHI), Melbourne, Australia; and the Institute
for Research in Biotechnology (UNSAM), Argentina.
The participation of an institution from a disease-
endemic country in this global consortium adds a novel
capacity-building dimension.
In addition to the above, a recent drug discovery
collaboration between Pfizer and WHO/TDR is being
extended to include support for the target portfolio
project. Pfizer is already supporting this network by
bringing its own genome triaging expertise and tech-
niques
36
to bear on the selection and prioritization of
molecular targets. A recent publication on target priori-
tization for Mycobacterium tuberculosis
55
demonstrates
the utility of this exercise across tropical diseases. Pfizer
is working with the University of Pennsylvania, the
University of California San Francisco Sandler Center,
and Inpharmatica to identify parasite homologues of
their own commercial targets for other indications. The
‘druggability’ of such parasite targets will be assessed and
ranked in order to facilitate prioritization by the drug
target network. The triaged information will be made
available through a database that is being developed by
the network. The synergistic, overlapping and coordi-
nated activities of the different groups present an oppor-
tunity for building a chemoinformatics and in silico drug
discovery platform for tropical diseases.
Compound screening and evaluation network. The
biological assessment network has been the engine of
TDR’s drug discovery strategy for many years. It is a
unique integrated global collection of compound assess-
ment centres that allows scientists from academia and
industry to submit compounds for test free of charge.
This has given the network unrivalled access to many
thousands of diverse compounds in the search for new
antiparasitic leads. However, in the process of assessing
these diverse collections, various recurring problems
have been noted. For example, the turn-around time has
been a contentious issue, particularly with the assess-
ment of individual compounds or small collections.
This arises because of the need of the screening centres
to amass sufficient samples to make it time-effective
to run multiple parasite assays at once. However, the
screening centres are now focused on evaluating agreed
numbers of compounds based on available budgets
to ensure an efficient turn-around of data. Another
problem encountered is that many samples supplied
for test and subsequently found active enough to jus-
tify progression have not been available in sufficient
quantity. Consequently, only preliminary test data have
Box 1 | Definitions and activity criteria for hits and leads:
Hit activity criteria for protozoa
• Plasmodium falciparum (K1) IC
50
<0.2 μg per ml, SI*>100
• Trypanosoma brucei rhodesiense (STIB 900) IC
50
<0.2 μg per ml, SI* >100
• Trypanosoma cruzi (Tulahuen) IC
50
<1.0 μg per ml, SI* >50
• Leishmania donovani (L82)
Axenic amastigotes IC
50
<0.5 μg per ml, SI* >20
Amastigotes in macrophage IC
50
<1 μg per ml, SI* >20
SI* = IC
50
L-6/IC
50
parasite
Lead activity criteria for protozoa
• Active in vivo (mice) in 10% dimethyl sulphoxide (DMSO) formulation at n × ≤100 mg
per kg as measured by >90% reduction in parasitaemia* and/or increase in life span**;
n = number of doses given intraperitoneally, subcutaneously or per orally daily, and
varies usually from 1–5
Malaria: Plasmodium berghei (ANKA strain), usually at 4 × 50 mg per kg*
,
**
African trypanosomiasis: T. b. brucei (STIB 795 strain), usually at 4 × 50 mg per kg*
,
**
American trypanosomiasis: T. cruzi (Tulahuen)**
Leishmaniasis: L. donovani (HU3)*
• Not overtly toxic in animals at efficacious dose
• Active in vitro against relevant parasite strains (for example, drug-resistant)
Hit activity criteria for helminths
• Schistosomiasis: Schistosoma mansoni adults 100% inhibition of motility at 5 μg per ml
• Onchocerciasis: Onchocerca lienalis mf 100% inhibition of motility at 1.25 × 10
–5
M
Onchocerca gutturosa adults 100% inhibition of motility or formazan formation at
1.25 × 10
–5
M with no obvious sign of toxicity to the monkey kidney feeder cell layer
Lead activity criteria for helminths
• Active in vivo (mice) when given intraperitoneally or subcutaneously in 10% DMSO
formulation at 5 × 100 mg per kg as measured by a statistically significant reduction in
worms (>80% is highly active)
Schistosomiasis: S. mansoni adults
Onchocerciasis: O. lienalis mf
• Not overtly toxic in animals at efficacious dose
Values are illustrative and are based on experience with compounds that have moved through
the evaluation network
5
.
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been obtained, which, once provided to the supplier,
have often been published without any further action
being planned. There is now increasing due diligence
being performed to assess the quality of the compounds
supplied for test and to ascertain that a commitment to
follow them up will be made by the supplier.
The investigators responsible for the individual test
centres funded by TDR are world-renowned parasitolo-
gists. Collectively, they offer a comprehensive range of
in vitro (whole parasite) screens and animal disease
models, permitting in-depth profiling against a range
of parasites and detailed assessment in various in vivo
systems to guide lead identification/optimization
(FIG. 2).
The network consists of five centres: the Swiss Tropical
Institute (STI), Basel, which provides in vitro and
in vivo screens for malaria, African trypanosomiasis,
leishmaniasis and Chagas disease; the London School of
Hygiene and Tropical Medicine (LSHTM), which pro-
vides in vitro and in vivo screens for schistosomiasis, as
well as in vivo assays for leishmaniasis and Chagas dis-
ease; the Northwick Park Institute for Medical Research
(NPIMR), London, which provides in vitro and in vivo
screens for filariasis and onchocerciasis; the Theodor
Bilharz Research Institute (TBRI), Cairo, which provides
Table 3 | Academic and public institutes offering drug screening opportunities for tropical and other diseases
Region HTS screens Whole-parasite screening and disease type
North
America
• NIH USA: Chemical Genomics Initiative and Molecular Libraries
Screening Center Network (http://nihroadmap.nih.gov)
• University of California San Francisco Sandler Center and
Tropical Diseases Research (http://www.ucsf.edu/mckerrow/
protocol.html)
• Harvard and Broad Institute Initiative (www.broad.harvard.edu/
chembio/plaform/screening/index.htm)
• Stanford University: High Throughput-Bioscience Center
(http://www.htbc.stanford.edu)
• Purdue Center for Combinatorial Chemical Biology
(http://www.chem.purdue.edu/CCCB/index/shtml)
• Yale University: Chemical Genomics (http://www.yale.edu)
• St. Jude Children’s Research Hospital HTS efforts
(http://www.stjude.org).
• McGill University: HTS facility (www.medicine.mcgill.
ca.biochem/htsfacility/index.htm)
• McMaster: HTS lab (www.hts.mcmaster.ca)
• Canadian Institute for Health Research, network for chemical
biology (http://www.cihr.irsc.gc.ca/e/28269.html)
• Walter Reed Army Institute for Research WRAIR — malaria,
leishmaniasis and others (http://wrair-www.army.mil/)
• University of Washington Seattle — malaria, trypanosomiasis
(http://depts.washington.edu/daid/)
• University of California San Francisco — malaria,
trypanosomiasis (http://www.ucsf.edu/)
• University of Mississippi — malaria, leishmaniasis
(http://www.pharmacy.olemiss.edu/ncnpr/)
• University of Southern Florida — malaria
Europe • University of Dundee Drug Discovery Initiative
(http://www.welcome.ac.uk/doc_wtx027342.html)
• European Molecular biology Laboratory: Chemical Genomics
Core Facility (http://www.embl.org)
• HT-Technology Development Studio, Max Planck Institute
(http://tds.mpi-cbg.de/webtds/4.html)
• Medical Research Council London — malaria
(http://www.mrctechnology.org)
• WISDOM: Initiative for grid-enabled drug discovery against
neglected diseases (http://wisdom.healthgrid.org/)
• Swiss Tropical Institute — malaria, leishmaniasis, trypanosomiasis,
helminths (www.sti.ch)
• London School of Hygiene and Tropical Medicine — malaria,
leishmaniasis, trypanosomiasis, schistosomiais (www.lshtm.ac.uk)
• Northwick Park Institute for Medical Research — filariasis,
onchocerchiasis
• Institute Pasteur — malaria, trypanosomiasis (http://www.pasteur.fr)
• University of Anwerp, Laboratory of Microbiology, Parasitology and
Hygiene — malaria, trypanosomiasis, leishmaniasis
(http://www.ua.ac.be/lmph)
• University of Liverpool — malaria (www.liv.ac.uk)
Asia/
Australia
• Walter Eliza Hall Institute for Medical Research
(http://www.wehi.edu.au)
• Griffith University, Eskitis Institute (www.griffith.edu.au/
centers/eskitits/
• Kitasato Institute Japan — malaria, leishmaniasis, schistosomiasis
(www.kitasato.or.jp)
• Indian Central Drug Research Institute Lucknow — expertise on
malaria, leishmaniasis, filariasis (www.cdriindia.org)
• Institute of Parasitic Diseases Shanghai China — malaria,
schistosomiasis
• National Center for Genetic Engineering and Biotechnolgy,
Thailand — malaria, tuberculosis (http://www.biotec.or.th)
Africa
and
Middle
East
• Tel Aviv University: National center for HTS of Novel Bioactive
Compounds (http://www.tau.ac.il/~nchts/main.htm)
• Theodor Bilharz Research Institute Cairo — schistosomiais
(http://www.tbri.sci.eg/main.htm)
• Kenya Medical Research Institute — malaria, leishmaniasis
(http://www.kemri.org/kemri_centres.asp)
• University of Ibadan Nigeria — malaria (http://www.ui.edu.ng/)
South
America
• Instuto Oswaldo Cruz — malaria, trypanosomiasis
(www.ioc.fiocruz.br)
• Instituto Venezolono de Investigaciones Cientificas, Venezuela
— trypanosomiasis
• Institute for Advanced Scientific Investigation and High
Technology — malaria, leishmaniasis
Some of the institutions involved in high-throughput screening (HTS) are not primarily focused on tropical diseases (see also REF. 51). The list might not be exhaustive.
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in vitro and in vivo screens for schistosomiasis; and the
Laboratory for Microbiology, Parasitology and Hygiene
at the University of Antwerp (LMPH), which provides
in vitro screens for malaria, leishmaniasis and trypano-
somiasis. Overall, the network is capable of process-
ing about 20,000 compounds per annum through the
in vitro screens and evaluating approximately 1,000
compounds per annum in vivo, based on the funding
currently provided by WHO/TDR. The turn-around
time for generating data varies for the various in vitro
and in vivo models used. On average, most in vitro test
data is available within 4–8 weeks of receiving the com-
pound whilst the turn around time for in vivo assessment
is about 8 weeks.
The compounds fed into these centres are sourced
from both industrial and academic partners and in
most cases the supply is under contractual agreement.
In recent years, hits emerging from these screens
have largely been pursued through the acquisition of
analogues, either from the original suppliers or from
commercial purveyors of compound libraries. Although
this has allowed development of preliminary structure–
activity relationships, often it has not allowed the work
to progress sufficiently to allow identification of lead
compounds that are orally efficacious in animal disease
models. The lack of a coordinated strategy encompass-
ing medicinal chemistry, pharmacology and toxicology
is now being addressed — active compounds are further
supported through the TDR medicinal chemistry and
pharmacokinetic networks in order to optimize activity
and generate robust leads. The activity criteria used for
some of these screens are presented in
BOX 1.
There are other well-established screening centres
for various tropical diseases
(TABLE 3), although these
tend not to cover the range of parasite assays embraced
by the TDR network. These include the Walter Reed
Army Institute for Research (WRAIR), which has
worked closely with TDR for many years in seeking
antimalarial leads; the Indian Central Drug Research
Institute, Lucknow; the Kitasato Institute, Japan; the
Institute for Parasitic Diseases, China; the University
of Washington, the University of North Carolina, the
University of Mississippi and the University of California
San Francisco, USA.
Database and compound storage resource in project
management. Another important element in the man-
agement of network and partnership activities is the
use of a secure interactive database for data, project and
communication management. The database managed
centrally by TDR enables the organization, collation
and management of all compounds sourced as well as
the resultant data subsequently generated from the test
centres. Compounds are organized with clear identifi-
cation numbers. A planned update of the TDR database
will enable relevant partners to enter data directly onto
the database from a remote location using a pass-
word-protected mechanism. The database promotes
enhanced communication, as recent results or presen-
tations can be shared as needed with relevant partners
at different locations in real time — for example, during
tele- or video conferencing. The integrated database
is secure and respects all confidential structures from
collaborators. Another equally important type of data-
base is the open-source database that contains various
research reagents
67,68
.
Linked to the function of the database is a central
compound storage facility where all the samples sourced
by TDR are collated and distributed to screeners in an
appropriate format. For the past few years, TDR has
retained RCC, Basel
(TABLE 4), as its compound storage
facility. The need for various types of databases
(whether secure or open-source) as well as compound
management
69,70
and storage exemplifies additional
elements of managing virtual drug discovery that are
not often discussed.
STI – Basel:
Malaria, African
trypanosomiasis,
Chagas disease,
Leishmaniasis
NPIMR-London:
Filariasis
TBRI-Cairo and LSHTM:
Schistosomiasis.
LMPH-Antwerp:
Malaria, African
trypanosomiasis,
Leishmaniasis,
Chagas disease
STI – Basel:
Malaria, African
trypanosomiasis,
Chagas disease,
Leishmaniasis
NPIMR-London:
Filariasis
Medicinal chemistry and pharmacokinetics/metabolism
networks aligned with screening centres
TBRI-Cairo and LSHTM:
Schistosomiasis
LSHTM:
Leishmaniasis,
Chagas disease
Lead identification
Secondary in vivo assays
Hit identification
Primary and repeat
in vitro assays
Lead optimization
Follow-on studies
Figure 2 | WHO/TDR-funded compound evaluation network. The compound evaluation network performs primary
in vitro screens against the various parasites. Compounds that meet the in vitro activity and cytotoxicity criteria (‘hits’) are
progressed to in vivo analysis, and subsequently medicinal chemistry and pharmacokinetic analysis to identify ‘leads’.
LMPH, Laboratory of Microbiology, Parasitology and Hygiene (Antwerp); LSHTM, London School of Hygiene and Tropical
Medicine; NPIMR, Northwick Park Institute for Medical Research (London); STI, Swiss Tropical Institute (Basel);
TBRI, Theodor Bilharz Research Institute (Cairo); WHO/TDR, Special Programme for Research and Training in Tropical
Diseases at the World Health Organization. Activity criteria for ‘hits’ and ‘leads’ are presented in
BOX 1.
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The medicinal chemistry and pharmacokinetics/
metabolism networks. The medicinal chemistry effort
currently involves one large pharmaceutical company
(Pfizer) partnering with TDR, and two biopharmaceu-
tical companies, Serono and Pharmacopeia
(TABLE 5).
Several academic institutions are also part of this net-
work: the University of Nebraska, USA; University of
Dundee, UK; University of Cape Town, South Africa;
Ohio State University, USA; and St. Jude Children’s
Research Hospital, Memphis, USA. These centres work
on the active compounds emerging from either the
screening network (whole cells) or from the HTS cam-
paigns (protein-based assays directed towards specific
molecular targets). Some of the recent active compounds
(validated hits) emerging from TDRs screening of com-
mercially sourced compounds are part of the series being
progressed through the medicinal chemistry network.
These include seven leads for various tropical diseases:
four for malaria, one for leishmaniasis, one for African
sleeping sickness and two for helminths.
The network seeks to carry out medicinal chemistry
using postdoctoral fellows based at those centres. These
pursue ‘hit to lead’ or early stage ‘lead optimization’ in
the normal iterative cycle of synthesis and biological
assessment, feeding compounds back into the screen-
ing centres
(FIG. 1). A number of fellows are linked to
institutions in developing countries. The participation
of a first-rate medicinal chemistry laboratory in a dis-
ease-endemic country provides an opportunity for the
establishment in Africa of a centre of excellence to help
promote innovation in this core area of lead discovery.
The pharmacokinetics/metabolism network, which
provides essential data for the chemists, presently con-
sists of the Monash University, Australia, and various
TDR collaborating companies such as Pfizer, Serono and
Pharmacopeia that are providing this service in-kind as
part of the ongoing collaboration. Additional academic
centres are being sought to augment this network.
Another approach to providing chemical support for
tropical disease research (one widely used by large pharma
for other therapeutic areas) is to draw on the services of
contract research organizations and institutions located in
advanced developing countries such as India and China
54
.
These are probably most productively deployed to syn-
thesize focused chemical libraries rather than engaging
in the more specific process of lead optimization. In
general, it will be beneficial to establish coordination
mechanisms similar to the integrated approach discussed
in this paper, to help harness the huge resources available
in these technologically advanced developing countries.
The risk of poor commercial return might explain why
some companies in these countries are not investing in
product discovery for tropical diseases endemic to these
geographic regions. However, an increasing number
of companies in China, India, Korea, South Africa and
Singapore are participating in PPPs to develop products
for various developing world diseases
2,9
.
Partnership characteristics and opportunities
The past 6 years has witnessed a dramatic increase in
interest in R&D directed towards producing new drugs
for tropical diseases. This has been fuelled by the creation
of various partnerships involving academia, industry and
PPPs, and the arrival of new funding from both govern-
ments and philanthropic foundations, in particular the
Gates, Wellcome Trust and Rockefeller Foundations
2,56
(
BOX 2; TABLE 6). Industry is increasing its participation
2,9
:
GSK has dedicated its Tres Cantos facility in Spain to
developing world diseases (mainly malaria and tuber-
culosis) and continues to collaborate with MMV and
GATB; the Novartis Institute in Singapore is focusing
on tuberculosis (in partnership with GATB) and den-
gue and has recently extended to malaria in partnership
with MMV and the Wellcome Trust; AstraZeneca India
is investing in tuberculosis drug R&D, as is Johnson &
Johnson; and Sanofi-Aventis has established an Impact
Malaria programme and continues to collaborate with
TDR and DNDi.
These efforts are required to sustain the drug devel-
opment pipeline for tropical diseases in the medium and
long term. In addition, drug R&D for certain diseases
Table 4 | TDR drug discovery collaborations
Name of company Type of business Type of collaborations with TDR
Pfizer Pharma/animal health • Compound supply for testing
• Medicinal chemistry/
pharmacokinetics
• Potential HTS campaigns
• Cheminformatics
• Training
Serono Pharma
• HTS campaigns
• Medicinal chemistry/
pharmacokinetics
• Training
Bayer Pharma/Animal Health
• Compound supply for testing
Sanofi-Aventis Pharma
• Compound supply for testing
• Other collaboration
Pharmacopeia Pharma
• Medicinal chemistry/
pharmacokinetics
• Training
TopoTarget Pharma
• Compound supply for testing
• Lead optimization for malaria
Paratek Pharma
• Compound supply for testing
Meiji Pharma/Animal health
• Compound supply for testing
Chemtura Crop protection/vector
control
• Compound supply for testing
Syngenta Agrochemicals • Compound supply for testing
Dow AgroSciences Agrochemicals
• Compound supply for testing
ChemDiv Chemical libraries and
contract synthesis
• Compound supply for testing
Princeton
BioMolecular
Research
Chemical libraries and
contract synthesis
• Compound supply for testing
Specs Chemical libraries and
contract synthesis
• Compound supply for testing
ChemRoutes Chemical libraries and
contract synthesis
• Compound supply for testing
RCC Contract Research • Compound storage and handling
HTS, high-throughput screening.
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continues to be neglected, such as those encompassed
by kinetoplastids (which DNDi is investing in, as well
as helminth infections, for which a new initiative is
being created
(BOX 3)). In a new development, Pfizer has
recently signed an agreement with the WHO/TDR to
provide compounds and other drug discovery support to
help identify leads for a wide range of tropical diseases:
malaria, African sleeping sickness, Chagas, leishma-
niasis, lymphatic filariasis, onchocerciasis and schisto-
somiasis. A similar collaboration directed at progressing
various HTS campaigns has been secured with Serono.
These new partnerships present a unique opportunity
for tropical diseases and will probably help draw other
companies into this field of research.
The recent re-emergence of interest in tropical dis-
ease research from the pharmaceutical sector is also
supported by the involvement of the animal health and
agrochemical industries, as well as specialty chemical
companies, who are all contributing compounds for
evaluation for human infectious diseases. This is exem-
plified by the collaboration of WHO/TDR with such
companies as Syngenta, Chemtura and Bayer Animal
Health
(TABLE 4). Forte Dodge is partnering with TDR in
clinically progressing the animal-health product moxid-
ectin for the treatment of onchocerciasis
24
.
Although TDR maintains a network of screening
centres with a substantial overall capacity for testing com-
pounds in whole-cell screens, it can be difficult to source
samples with an appropriate rationale for testing and in
sufficient quantity to facilitate follow-up assessment.
Increasing efforts are being put into sourcing high-quality
compounds with a defined testing rationale. Companies
are sought that might have biologically, biochemically or
pharmacophore-relevant compounds that they would be
willing to provide for assessment for their potential to
treat tropical diseases. Experience shows that although
many scientists in industry are extremely willing to
provide compounds for testing, higher management is
often more reticent due to perceived problems in expos-
ing their intellectual property to competitors or putting
at risk drugs in commercial development. Such issues,
although often requiring protracted discussion, can
usually be addressed satisfactorily, and TDR plus other
PPPs have been successful in establishing agreements
with industry to enable them to partner and contribute
compounds for evaluation against tropical diseases.
Partnerships for drug discovery with both industry
and academia typically involve the following: the supply
of biologically or biochemically relevant compounds,
or natural products, for screening against parasites;
supporting investigators to validate and obtain pro-
teins as molecular targets for HTS campaigns; access-
ing or supporting centres to conduct HTS campaigns
using diverse or focused compound libraries; funding
medicinal chemistry, pharmacokinetics/metabolism and
toxicological assessment for lead identification and opti-
mization, as well as supporting the establishment and
maintenance of databases to facilitate drug discovery for
tropical diseases.
These collaborations are normally covered by ‘materi-
als transfer’ or ‘collaborative’ contracts as exemplified by
the recent agreements between WHO/TDR and Pfizer,
Serono and Chemtura. The Pfizer collaboration focuses
initially on lead discovery, with the company supply-
ing thousands of compounds (including those with a
known biological/biochemical rationale) to be tested
against target parasites in TDR’s screening network. Hits
emerging from this programme will be expanded using
TDR-funded medicinal chemists based at Pfizer. The col-
laboration is being extended to pursue HTS campaigns
against molecular targets, and to use cheminformatics to
identify new targets and compounds
36,37,57
.
The Serono–WHO/TDR collaboration centres on
drug discovery through HTS campaigns and allows for
hit expansion with medicinal chemistry support. Serono
is using its compound libraries for HTS against putative
new drug targets selected by TDR in association with
collaborators based in academia. Hits identified in these
protein-based assays are assessed in the TDR parasite
screens. Whole-cell actives are then further elaborated
to develop SAR using TDR-funded medicinal chemistry
resources based in Serono. The Chemtura–WHO/TDR
agreement focuses initially on supply of test compounds.
These and other companies helping TDR in the discov-
ery of new leads are highlighted in
TABLE 4. Collectively,
these represent a significant coordinated level of early
discovery activity for multiple tropical diseases.
The globally integrated and focused strategy depicted
in
FIG. 1 is helping to stimulate industry worldwide to
participate in lead discovery for tropical diseases. It is
also attracting more academic investigators to work in
the field of ‘neglected diseases’ drug discovery. It com-
plements and synergizes with the activities of PPPs such
as MMV, DNDi and GATB by facilitating the progres-
sion of new leads into the development pipeline of these
organizations or other institutions. It is noteworthy that a
number of lead series currently being developed by PPPs
benefited from initial involvement with WHO/TDR,
either by direct support for synthesis programmes or by
access to the compound-assessment network. Examples
include the antimalarial ozonides
7
, bis-amidines
49
and
dihydrofolate reductase inhibitors
39
being developed by
Table 5 | The medicinal chemistry network
Workstations (pharma/
academia)
Number of post-
doctoral fellows
Pfizer Two fellows
Serono Two fellows
Pharmacopeia One fellow
University Cape Town Two fellows
University of Nebraska One fellow
University of Dundee One fellow
St Jude Children Hospital One fellow
Ohio State University One fellow
Some of the postdoctoral fellows are from disease-endemic
countries. They receive on-the-job training in order to
contribute to specific projects in the network. The interface
between medicinal chemistry and the networks engaged in
compounds assessment and pharmacokinetic profiling is
managed jointly by WHO/TDR and partners.
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MMV, and trypanothione reductase
16
and farnesyltrans-
ferase inhibitors
58
previously supported by DNDi. This
has provided these organizations with sufficient data to
allow critical assessment of the work and to commence
funding at the lead optimization stage.
Arguably, one of the more novel and attractive ele-
ments of this innovative lead discovery approach is the
integration of capacity building through clear project
deliverables. Such capacity building in lead discovery, as
shown in
FIG. 1, is not restricted to the developing world
— through network activities it can also be pursued in
institutions in developed countries. In the context of
disease-endemic countries, this approach will encourage
local technology development — for example, through
exploration of natural products as potential leads, and
technology transfer through the various network activi-
ties. TDR is supporting two natural-product screening
centres in Kenya and Nigeria. Sustainable capacity can
be developed in disease-endemic countries if the most
talented scientists and institutions are engaged in these
partnerships for lead discovery with the same level of
rigour as their colleagues in developed countries. In
Box 2 | Synergies of partners in lead discovery for tropical diseases
Academia. The role of academic laboratories is indispensable in lead discovery for tropical diseases. Tropical disease
expertise in in vitro and in vivo screening
(TABLE 3), development of new screening tools, improved animal models,
genomics, and target identification/validation resides within academia. In addition, academic laboratories are making
great strides in high-throughput screening (HTS), medicinal chemistry and pharmacokinetic analysis to aid the
discovery and progression of leads into development candidates for tropical diseases, and this should be encouraged.
For example, TDR has collaborated with the Walter Eliza and Hall Institute for Medical Research in Melbourne to run
HTS against three parasite targets: trypanothione reductase (from Trypanosoma cruzi), farnesyl pyrophosphate
synthetase (Trypanosoma brucei) and pyrophosphokinase (Plasmodium falciparum). The initial hits emerging from the
three campaigns have been evaluated in whole parasites at the WHO/TDR compound screening centres, and follow-
up medicinal chemistry/pharmacokinetic studies are now under consideration. Similar HTS campaigns have been
commissioned by Drugs for Neglected Diseases Inititative (DNDi) at other academic institutions. Such laboratories
(TABLE 3), as discussed previously, are well established for HTS campaigns. Further participation from academia will
probably be encouraged by such success stories as the selection of a synthetic peroxide OZ277 by the Medicines for
Malaria Venture (MMV) for development for malaria (now in Phase II clinical trials)
7
. This involved participation from
both industry and academia, as well as input from experts with pharma experience. Although the increasing role of
academic centres in drug discovery for tropical diseases is a welcome development, partnership with industry and
other centres will help to maximize output.
Industry. TDR and the new private–public partnerships (PPPs) have a track record in collaborating with industry to identify
new drug candidates for human health
64
. Indeed, a focused lead discovery effort that incorporates a clear milestone-driven
approach and a ‘win–win’ intellectual property strategy promises to attract more industry involvement. Industry typically
provides compound libraries, infrastructure and know-how for HTS, medicinal chemistry and ADMET (absorption,
distribution, metabolism, excretion and toxicity) profiling. However, academia is increasingly starting to have a significant
role in the provision of chemistry and pharmacokinetic expertise and in developing HTS capabilities
7,34,35,53,64,65
.
TDR or other public-sector participants typically bring knowledge of the disease and target product profile to guide
discovery, molecular targets for screening from academic collaborators and funding from its stakeholders to leverage the
investment of industry (for example, by funding personnel, including fellows from developing countries, to work on
projects as well as portfolio management).
PPPs. Some PPPs involved in tropical disease R&D
(TABLE 6) are focusing on product development with less investment in
the early stages of lead discovery (for example, HTS against molecular targets and medium-throughput screening against
parasites in vitro). Investment in early drug discovery is essential in order to ensure a sustainable portfolio of lead
compounds for further optimization and development. The focused lead discovery strategy and the work of academic
centres discussed here will complement and synergize with PPPs such as MMV, Global Alliance for TB Drug Development
(GATB)
and DNDi.
Philanthropic foundations. Organizations such as the Bill and Melinda Gates Foundation, Rockefeller Foundation and the
Wellcome Trust are investing in discovery
(TABLE 6). They make funding available for such work as long as a clear
rationale exists supported by the appropriate technical and management expertise to achieve agreed objectives. Some of
the projects supported through the Gates Grand Challenges initiative should help to stimulate lead discovery in the
medium to long term. In response to the gap in the availability of new tuberculosis leads, the Gates Foundation has
developed a new strategy for tuberculosis drug discovery, which is much needed (See Further information, Bill & Melinda
Gates Foundation: Call For Proposals — Tuberculosis). It would seem that the strategy for this programme is similar in many
respects to the network and partnership approach discussed in this paper. It is anticipated that the target prioritization
exercise discussed above, which encompasses tuberculosis (see also
REF. 55), will complement this new effort.
In addition to supporting the University of Dundee’s drug discovery efforts, the Wellcome Trust is also funding a more
general initiative focused on early stages of lead discovery/optimization. However, this is not directed specifically towards
tropical diseases and can encompass any human disease.
National and international research agencies. Some national and international agencies
(TABLE 6) might have
opportunities for funding and capacity building in various areas of tropical diseases.
These various initiatives, some with varied scope, funding and strategy are an excellent demonstration of the progress
being made in tropical disease R&D. It also shows the need to increase coordination in order to better manage interfaces,
gaps and data flow from these efforts.
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contrast to past capacity-building activities in developing
countries, this approach is linked to clear project delivera-
bles, management and accountability. There have already
been some successes through the fellowship component
of this approach, with scientists involved with HTS cam-
paigns at Serono going back to their countries to put
their new-found experience into practice
59
.
Currently, global interest in the promotion of innova-
tion for new treatments for developing-world diseases
is high. The G8 meeting in 2005
(REF. 60), as well as the
Millennium Development Goals
61
, emphasize the role of
partnerships in providing worldwide healthcare solutions.
The WHO Commission on Intellectual Property Rights,
Innovation and Public Health also highlighted the need
for innovative product discovery for diseases affecting
developing countries
11
. Indeed, increased emphasis on
innovative lead discovery will help ensure sustainability
in the availability of new products for the control of tropi-
cal diseases both in the medium and long term. The hope
is that public donor agencies and foundations will invest
more resources in this area. Some recent indication of
such improved funding comes from a call from the Gates
Table 6 | Organizations funding (or likely to fund) research into tropical diseases
Organization Website
Philanthropic foundations
Bill & Melinda Gates Foundations http://www.gatesfoundation.org
Burroughs Wellcome http://www.bwfund.org
Grand Challenges http://www.grandchallengesgh.org
Rockefeller Foundation http://www.rockfound.org
Wellcome Trust http://www.wellcome.ac.uk
Public organizations/institutions*
European Union http://ec.europa.eu/research/health/poverty-diseases
UK DFID http://www.dfid.gov.uk/research
US National Institute of Health http://www.nih.gov; http://www.niaid.nih.gov
International Development Research Council Canada http://www.idrc.ca
Canadian Institute for Health Research http://www.cihr-irsc.gc.ca
Public–private partnerships
Drugs for Neglected Diseases Initiative http://www.dndi.org
Global Alliance for TB Drug development http://www.tballiance.org
Medicines for Malaria Venture http://www.mmv.org
Institute for One World Health http://www.iowh.org
International organizations and development banks
Special Programme for Research and Training (TDR) at WHO http://www.who.int/tdr
The World Bank http://www.worldbank.org
Regional Development Bank http://www.iadb.org; http://www.afdb.org;
http://www.adb.org
United Nations Education, Scientific and Cultural
Organization (UNESCO)
http://www.unesco.org
This list is not exhaustive. *Certain national agencies concerned with international development and research such as United
States Agency for International Development USAID (www.usaid.gov), Japan International Cooperation Agency JICA
(http://www.jica.go.jp), Swedish International Development Agency (http://www.sida.se), German Agency for Technical
cooperation (http://www.gtz.de/home/english), Swiss Agency for Development and Cooperation (www.sdc.admin.ch),
Danish International Development Agency DANIDA, Canadian International Development Agency (www.cida.gc.ca), Netherlands
Ministry of Development Cooperation, and other national as well as research councils and ministers.
Foundation for proposals for discovery research directed
towards TB (see Further information, Bill & Melinda
Gates Foundation: Call For Proposals — Tuberculosis).
In view of the changing nature of drug research for
tropical diseases, more robust coordination mechanisms
are needed for lead discovery. A promising vehicle for
delivering and coordinating the discovery of new lead
compounds is exemplified by the integrated networks
embracing compound screening, medicinal chemistry,
pharmacokinetics/metabolism, and the development of
a prioritized drug target portfolio
(FIG. 1). This strategy
offers a cost-effective solution to filling the demand for
robust lead compounds suitable for further develop-
ment
62,63
. Initial cost assessment based on TDR’s lead
discovery experience using the network and partnership
method described here suggests that two high-quality
lead compounds can be discovered every year with an
annual budget of about US$7 million. This includes
investment in the development of new technologies
— such as new drug screening tools and prioritization
of drug targets to facilitate HTS campaigns, as well as
capacity building — that will help sustain lead discovery
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for tropical diseases in the medium to long term. This is
good value for money considering the high attrition rate
in early drug discovery. Obviously this estimate does not
include in-kind contributions from the industry.
Challenges of lead discovery
Managing multiple partners (FIG. 1; BOX 2) from diverse
cultures and with a wide range of expertise in a network
charged with a unique drug discovery objective is not an
easy undertaking
2,21
. The success of these networks largely
depends on the people doing the work, the available
facilities, the mechanism(s) put in place for programme
management by the coordinating body and the incentives
provided for reaching defined goals. Perhaps the single
most important stimulus is the appreciation that the work
being performed is for the public good, not for profit.
Many scientists in industry are willing to contribute their
expertise to help advance projects focused on developing-
world diseases. This is also true of academic scientists
who are increasingly pursuing product-driven research
for tropical diseases even though it is often perceived to
be less rewarding in terms of career prospects than some
of the more fashionable healthcare issues. Attracting
younger academic investigators into this field will require
an increase in targeted funding. However, good science
alone is not sufficient to ensure success — in all the
programmes discussed the science has to be supported
by strong management. In this context, the importance
of a project champion cannot be overemphasized, and
without such a leader many promising avenues of drug
discovery will fail to make progress. The overall balance
of good science, appropriate funding, enthusiasm and
clear management will determine the outcome of all
science-based programmes.
It should also be noted that a key element in success-
fully managing virtual drug discovery is flexibility in
decision making
2
. This includes the ability to prioritize
projects, re-allocate resources and terminate projects that
are not going well. However, the industry mantra ‘kill
quick, kill cheap’ often does not find ready acceptance
in an academic setting, and the different management
styles resulting from the varying cultural experience of
all the partners (academia, industry and donors) in a net-
work/partnership setting can sometimes cause difficulty
in decision making.
Mitigation of risks in lead discovery
Lead discovery is an inherently high-risk activity, as
demonstrated by the corresponding attrition rates. Some
of the challenges highlighted above can be overcome
through the establishment of clear processes for project
and portfolio management in order to deliver lead dis-
covery objectives. The need for competitive project selec-
tion and review procedure by external experts promises
to reduce attrition and the cost of lead discovery. Expert
scientists from academia and industry are readily avail-
able to support and invest their time at no or limited
cost for the purposes of reviewing and recommending
promising projects for such endeavours.
A clear understanding of tropical diseases, desired
product profiles for new drugs to guide R&D, and the
needs of disease-endemic countries, are key to the dis-
covery of relevant molecules for further development
2
.
The use of focused target product profiles
(TABLE 1)
to guide lead discovery and development candidate
selection increases the chances of successful control pro-
grammes if and when such products reach the market.
The focus on innovative lead discovery fills a crucial
gap in the tropical diseases drug development pipeline.
The plan recognizes the important role of partnerships,
as well as the participation of developing country scien-
tists and institutions, in order to achieve the Millennium
Development Goals and to provide a lasting solution to
the product-access crises.
Box 3 | A new initiative focusing on helminth drug discovery
In recognition of the urgent need for new anthelminthics, WHO/TDR is currently
coordinating and facilitating drug discovery for helminth infections. An informal
consultation meeting convened by TDR in February 2005 identified the need for an
initiative to facilitate the discovery and development of new products for diseases
resulting from infections with schistosoma and the filariae. The Genomics and Discovery
Research committee of TDR endorsed proceeding with such an initiative but
recommended that a focused meeting of world experts from industry, academia and the
donor community be convened to provide further guidance. Subsequently, the meeting
was held in Tokyo in March 2006 and the concept of the helminth initiative fully
endorsed. TDR was tasked with the establishment and incubation of the Helminth
Initiative, focusing on antihelminthic drug discovery to identify new candidates that can
be advanced to development. It is expected that success in the next 2–3 years might help
to build a case for an independent public–private partnership for anthelminthic R&D.
Genomics HTS
Lead ID
(in vitro/in vivo
test, medicinal
chemistry, PK)
Lead
optimization
Preclinical
development
Malaria:
four lead series
WEHI:
three targets
Pfizer collaboration
Helminth initiative
Serono collaboration
Portfolio
of drug
targets and
database
being
developed
African
trypanosomiasis:
one lead series
Leishmaniasis:
one lead series
Helminths:
one lead series
HDAC
inhibition for
malaria
Figure 3 | The growing WHO/TDR drug discovery portfolio. Molecular targets being
pursued as part of the Serono/TDR collaboration include: a Plasmodium falciparum serine
protease, PfSub-1, provided by M. Blackman (MRC, London), a P. falciparum Ca
2+
-dependent
protein kinase, PfCDK-1, supplied by B. Kappes (U. Heidelberg) and a cysteine peptidase
from Leishmania mexicana, LmCPB, provided by J. Mottram (University of Glasgow). The
targets pursued at WEHI include Trypanosoma cruzi trypanothione reductase from A.
Fairlamb (University of Dundee), Trypanosoma brucei farnesyl pyrophosphate synthase
provided by E. Oldfield (Univeristy of Illinois), and P. falciparum pyrophosphokinase from
Sirawiraporn (Mahidol University). HDAC, histone deacetylase; WEHI, Walter Eliza and
Hall Institute for Medical Research; WHO/TDR, Special Programme for Research and
Training in Tropical Diseases at the World Health Organization.
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11
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countries will be the most important determinant of
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ate health-care technologies.” As the report goes on to
say, “The formation of effective networks, nationally
and internationally, between institutions in develop-
ing countries and developed countries, both formal
and informal, are an important element to building
innovative capacity. ” This reflects the views expressed
in this paper on the need for increased investment
in upstream drug discovery for tropical diseases.
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Acknowledgements
The authors would like to thank R. Ridley, A. Oduola and
J. Lazdins for their support, A. Fairlamb and T. Wells for
critically reading the manuscript. We also thank F. Fakorede,
M.-A. Mouries, C. Alias and L. Swarb for their help with
the paper.
Competing interests statement
The authors declare no competing financial interests.
FURTHER INFORMATION
Medicines for Malaria Venture: http://www.mmv.org
Grand Challenges in Global Health — Limit Drug Resistance:
http://www.gcgh.org/subcontent.aspx?SecID=396
EU Commission — Poverty-Related Diseases:
http://europe.eu.int/comm/research/health/poverty-
diseases/projects/124_en.htm
EU Commission — New TB Drugs: http://ec.europa.eu/
research/health/poverty-diseases/projects/130_en.htm
Bill & Melinda Gates Foundation: Call For Proposals –
Tuberculosis: http://www.gatesfoundation.org/
GlobalHealth/Grantseekers/RFP/RFP_TB.htm
Access to this links box is available online.
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