Acta Tropica 198 (2019) 105107

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Acta Tropica
journal homepage: www.elsevier.com/locate/actatropica

Drug discovery for chagas disease: A viewpoint T

Jadel Müller Kratz
⁎

Drugs for Neglected Diseases initiative (DNDi) Latin America, Rio de Janeiro, Brazil

ARTICLE INFO ABSTRACT

Keywords: Chagas disease is a neglected tropical disease caused by the protozoan parasite Trypanosoma cruzi. It is a sig-
Trypanosoma cruzi nificant public health problem, affecting millions of people worldwide. And although it was described 110 years
Chagas disease ago, only two old nitroheterocyclic drugs, benznidazole and nifurtimox, are currently available for the treatment
Drug discovery of Chagas disease and both have several limitations. Besides the clear unmet medical need, many challenges
preclude the development of new treatments, some of them related to a lack of understanding of the patho-
physiology of the disease and parasite-host interactions. New knowledge and tools are becoming available, but
the number of new chemical entities progressing through the preclinical pipeline is inadequate. Therefore, it is
still uncertain whether safe, effective and accessible new drugs will be available in the near future. The Chagas
disease research community must commit to even greater collaboration to ensure that patients eventually benefit
from better treatments.

1. Introduction
Chagas disease (CD), or American trypanosomiasis, is a neglected
tropical disease (NTD) caused by the protozoan parasite Trypanosoma
cruzi. Infection occurs by vectorial, congenital, iatrogenic or oral routes,
and the disease is characterized by two distinct clinical phases. CD
begins with an acute phase with detectable parasitaemia, usually
asymptomatic and undiagnosed, followed by a lifelong chronic phase
which can manifest as a variety of debilitating conditions. The chronic
phase is divided into chronic asymptomatic or indeterminate (char-
acterized by seropositivity for T. cruzi and absence of clinical signs), and
chronic symptomatic (encompassing around 30% of patients) (Pérez-
Molina and Molina, 2017; World Health Organization, 2012).
An estimated 6–7 million people are infected with T. cruzi world-
wide. CD is considered to be the parasitic disease with the greatest
socioeconomic impact in Latin America, causing over 800,000 dis-
ability-adjusted life years and around 7500 deaths per year (Lee et al.,
2013; World Health Organization, 2012). It is important to acknowl-
edge that both the number of new cases and the burden of CD in Latin
America have decreased substantially over recent years, mostly due to
the control of transmission by the vector and by transfusion (World
Health Organization, 2017).
However, the profile of CD has changed from a disease primarily
impacting rural areas of Latin America to a public health concern in
large cities, and in the United States, Canada, Europe, and elsewhere
(Briceño-León, 2009; Gascon et al., 2010). Several challenges remain,
such as poor access to diagnostics, the lack of timely tools to assess
parasitological cure, and the suboptimal profile of antitrypanosomal
drugs, which require extended treatment durations, have side effects
and are unable to eliminate all parasites in some patients (Chatelain,
2014; Dias et al., 2016; World Health Organization, 2012).
There is, therefore, a clear need for safe, effective, and accessible
new therapies for CD. In this short review, the current status and
challenges associated with drug discovery for CD are discussed. It
provides a personal viewpoint based on multiple discussions and col-
laborations with scientists from the Chagas community around the
globe.
2. Available drugs for Chagas disease
According to the World Health Organization (WHO), the goal of
treatment for CD is to eliminate the parasite from infected individuals,
thus decreasing the probability of developing symptomatic CD and
hindering parasite transmission (World Health Organization, 2012).
Only two old nitroheterocyclic drugs, benznidazole (BZN) and ni-
furtimox (NFX) (Fig. 1), are available for the treatment of CD. They
require prolonged treatment (60–90 days) and are primarily considered
effective for acute infections (including neonates or infants with con-
genital transmission), cases of reactivation during the chronic phase,
chronic patients up to 18 years old, and infected women of childbearing
age (administered concomitantly with contraceptive measures) (Kratz
et al., 2018).

⁎
Corresponding author at: Drugs for Neglected Diseases initiative — Latin America, Rua São José, 70, Centro, Rio de Janeiro, RJ, 20.010-020, Brazil.
E-mail address: jkratz@dndi.org.

https://doi.org/10.1016/j.actatropica.2019.105107
Received 18 April 2019; Received in revised form 9 July 2019; Accepted 22 July 2019
Available online 24 July 2019
0001-706X/ © 2019 Elsevier B.V. All rights reserved.
J.M. Kratz
Fig. 1. Benchmark drugs benznidazole and nifurtimox, and representatives of new chemical classes under development for Chagas disease.
Treatment of patients with BZN has a very clear trypanocidal effect,
drastically reducing parasitaemia in both acute and chronic phases, but
in some cases, parasites persist and patients test positive for infection in
a subsequent screen (e.g. testing by PCR). In the adult population,
seroconversion (the decisive marker of parasite clearance) can take
years to decades after treatment, making it difficult to establish a “proof
of cure” in this population (Chatelain, 2017; Kratz et al., 2018; Morillo
et al., 2015; Torrico et al., 2018).
Thus, the efficacy of BZN in the chronic indeterminate adult po-
pulation, and its potential to preclude the development of cardiomyo-
pathies or gastrointestinal pathologies, are still a matter of intense de-
bate (Chatelain, 2017; Morillo et al., 2015). There is a growing body of
evidence, mostly from observational studies, that both BZN and NFX
reduce morbidity and mortality when administered to adults with
chronic CD (Cardoso et al., 2018; Fabbro et al., 2007; Viotti et al.,
2006). Therefore, WHO recommends the treatment be offered to
chronically infected patients (Dias et al., 2016; Pan American Health
Organization, 2019; Kratz et al., 2018; World Health Organization,
2012).
In addition to inadequate efficacy, the current drugs for CD have
several other limitations that substantially restrict their use. Their
supply is insufficient, both are contraindicated during pregnancy due to
genotoxic effects, and treatment produces adverse effects, mostly cu-
taneous (BZN) and gastrointestinal (NFX), with treatment dis-
continuation rates typically ranging from 15 to 20% (Kratz et al., 2018;
Molina et al., 2015; Morillo et al., 2015).
3. Drug discovery pipeline
Drug discovery for NTDs is a very demanding field, and the chal-
lenges associated with it have recently been reviewed in several pub-
lications (Burrows et al., 2014; De Rycker et al., 2018; Field et al., 2017;
Rao et al., 2019). CD drug discovery scientists face many particular
challenges, mainly linked to the variety of unanswered questions re-
garding both the disease itself and parasite-host interactions. The recent
disappointing results of clinical trials evaluating CYP51 inhibitors
(azoles targeting T. cruzi ergosterol synthesis pathway) – posaconazole
(Molina et al., 2014) and fosravuconazole (Torrico et al., 2018) –
highlight the colossal challenge of drug discovery for kinetoplastid
diseases.
Although CD was described 110 years ago by the Brazilian re-
searcher Carlos Chagas, little is known about the factors influencing the
progression of the disease and the development of clinical
2
Acta Tropica 198 (2019) 105107
manifestations. Ultimately, for drug discovery campaigns, it is still
unclear what role immune response and parasite reactivation play in
the severity of the disease, and whether complete parasite clearance
after trypanocidal treatment will eventually lead to clinical benefits for
indeterminate chronic CD patients (Chatelain, 2017; Rao et al., 2019).
Nevertheless, chemotherapy with trypanocidal drugs remains the
foundation of all CD therapeutic strategies. To guide the development
of new treatments (either new chemical entities or improved regimens
of current drugs), it is fundamental to define a clear target product
profile (TPP), which describes the features required for the ideal final
product. In the case of new chemical entities, the TPP will also orient
the construction of screening cascades and the definition of compound
progression criteria (and eventually a target candidate profile – TCP)
used during early drug discovery. Several experts in the field have re-
cently published a TPP for CD (Rao et al., 2019), and another has been
developed by DNDi (Table 1) (Chatelain, 2014).
The first step of every drug discovery campaign is the identification
of chemical starting points (i.e. hit compounds) via screening of che-
mical libraries using either target-based or phenotypic-based ap-
proaches. In the NTD field, target-based programs are scarce due to
very few validated targets and the persistent gap between genetic and
chemical validation in trypanosomatids (Gilbert, 2013). Phenotypic- or
cell-based approaches remain the main focus for CD drug discovery,
and several assays have been described in the literature (Chatelain and
Ioset, 2018). Numerous compounds that have been identified using this
strategy have been recently reviewed (Scarim et al., 2018). Un-
fortunately, very few of them have progressed through lead optimiza-
tion into preclinical and/or clinical development.
In fact, the number of compounds currently in the later stages of the
preclinical pipeline is modest and represents only a few chemical
classes, such as nitroimidazoles (fexinidazole recently registered for
sleeping sickness and currently in Phase II clinical trials for CD), and the
pan-kinetoplastids benzoxaboroles (exemplified by AN4169/
SCYX6759) and proteasome inhibitors (exemplified by GNF6702)
(Fig. 1) (DNDi Portfolio, 2019; Khare et al., 2016; Moraes et al., 2014).
4. New tools and strategies
In order to improve the translation of current models used for CD
drug discovery, the research community must ensure there is a con-
tinuous effort to understand T. cruzi biology and CD pathophysiology,
while in parallel new and better tools are developed based on the
knowledge acquired. This synergistic approach is likely to generate
J.M. Kratz
Table 1
DNDi’s Chagas disease Target Product Profile (TPP).
Acceptable
Target population Chronic
Strains TcI, TcII, TcV and TcVIa
Distribution All areas
Adult / Children Adult
Clinical efficacy Non-inferior to benznidazole in all endemic regions (parasitological)
Safety Superiority to benznidazoleb
3 CE plus 2 standard LE or ECG during treatment
Activity against resistant strains Not necessary
Contraindications Pregnancy / Lactation
Precautions No genotoxicity; No proarrhythmic potential
Interactions No clinically significant interaction with anti-hypertensive, anti-
arrhythmic and anticoagulants drugs
Presentation Oral
Stability 3 years, climatic zone IV
Dosing regimen Comparable to systemic antifungal treatments
a
Classification according to (Zingales et al., 2009); requires further research for definition of target strains for evaluation.
b
CE, clinical evaluation; LE, laboratory evaluation; ECG, electrocardiogram.
opportunities that could accelerate the development of a new che-
motherapy for CD.
The impact of the information gathered during the investigation of
the failure of CYP51 inhibitors in Phase II trials is a classic example of
positive feedback from the clinical setting into early drug discovery.
New improved in vitro assays, including panels of T. cruzi strains and
clinical isolates (covering all current discrete typing units, which allows
the assessment of parasite genetic diversity to some extent), time-kill
and prolonged washout assays (which allow the differentiation between
nitroaromatic drugs and posaconazole), and CYP51 inhibition assays
are now part of screening cascades used to prioritize only the most
promising compounds (able to produce sterile cure in vitro) to be pro-
gressed into in vivo experiments (Cal et al., 2016; Chatelain and Ioset,
2018; MacLean et al., 2018; Moraes et al., 2014).
Additionally, transgenic parasites and bioluminescent imaging
techniques allow the live monitoring of parasitemia in mice and have
facilitated the development of new stringent murine models that can
also differentiate between BZN and posaconazole and might show
better translatability (Chatelain and Konar, 2015; Costa et al., 2018;
Lewis et al., 2014). Systematic improvement and validation of Chagas
models in higher order mammals, such as dogs or non-human primates,
that more closely reflect the human disease (Diniz et al., 2010; Guedes
et al., 2002; Rosner et al., 1988), is highly desirable. The combination
of different animal models might allow a better understanding of
parasite tissue tropism, establishment of PK/PD relationships (one of
the main hurdles in CD drug discovery), and determination of im-
munological responses to treatment, and, in theory, improve the pre-
dictability of drug candidate efficacy (Chatelain and Konar, 2015).
A dormant form of T. cruzi was recently identified (Sánchez-Valdéz
et al., 2018). These non-replicating forms persist after treatment with
BZN (up to 30 days) and might help to explain the variability in the
efficacy of current drugs, which are typically highly effective in redu-
cing parasitemia but show variable rates of seroconversion and con-
version to negative PCR (Kratz et al., 2018; Morillo et al., 2015; Yun
et al., 2009). New tools that would allow screening of compounds
against “persistent” forms are highly desirable but may prove difficult
to achieve, and their feasibility has yet to be assessed.
The identification of new molecular targets, via target discovery
using genetic approaches and/or via target deconvolution of pheno-
typic hits, can also have a positive impact in CD drug discovery. The use
of target-based approaches in combination with modern drug discovery
technologies, such as DNA encoded libraries (Neri, 2017) and ultra-
large in silico screenings (Lyu et al., 2019), might enable the assessment
3
Acta Tropica 198 (2019) 105107
Ideal
Chronic and Acute (Reactivation)
Alla
All areas
All
Superiority to benznidazole in different phases of disease (acute and
chronic) (parasitological)
Superiority to benznidazole or nifurtimox
No CE or LE or ECG needed during treatment
Active against nitrofuran- and nitroimidazole-resistant T. cruzi
strains
None
No genotoxicity; No teratogenicity; No negative inotropic effect; No
proarrhythmic potential
None
Oral
5 years, climatic zone IV
Once daily / 30 days
of targets druggability and the identification of novel chemotypes in a
larger scale, and in parallel provide additional tools for their optimi-
zation into preclinical and clinical candidates.
Other approaches that are consolidated and/or expanding in other
therapeutic areas might also play a key future role in CD drug dis-
covery, including prophylactic and therapeutic vaccines (Beaumier
et al., 2016; Portillo et al., 2019), drug combinations (Ashley and Phyo,
2018; Tyers and Wright, 2019), immunomodulation and adjunct
therapies (DNDi Portfolio, 2019; Pahlajani et al., 2016), and covalent
inhibitors (Ghosh et al., 2019).
5. Conclusion
In view of recent progress and the remaining challenges associated
with CD drug discovery, the likelihood of a new optimal treatment for
CD arising in the next few years remains uncertain. Nonetheless, it is
clear that the success of a drug discovery enterprise does not depend
solely on the implementation of new tools and technologies, but also on
the availability of robust funding and collaborative R&D models, and a
better understanding of the pathophysiology of the disease (Chatelain,
2017; Chatelain and Ioset, 2011; Ferrins and Pollastri, 2018; Furtado
et al., 2014; Rao et al., 2019). Therefore, the Chagas community must
continuously advocate for even greater support and collaboration, and
keep progressing drug discovery projects (with new chemical series and
complementary approaches) in parallel with a large-scale collective
effort to answer basic questions about CD.
Funding source
DNDi is grateful to its donors, public and private, who have pro-
vided funding for all DNDi activities since its inception in 2003. A full
list of DNDi’s donors can be found at http://www.dndi.org/donors/
donors/.
Declaration of Competing Interest
The author is an employee of DNDi. The author has no other re-
levant affiliations or financial involvement with any organization or
entity with a financial interest in or financial conflict with the subject
matter or materials discussed in the manuscript apart from those dis-
closed.
J.M. Kratz
Acknowledgments
Thanks to DNDi colleagues and partners for inspiring discussions
around drug discovery for neglected tropical diseases. Special thanks to
Colin Forsyth and Louise Burrows for critical reading and reviewing of
this manuscript.
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