The translational challenge in Chagas disease drug development

Chagas disease is a neglected tropical disease caused by the protozoan parasite Trypanosoma cruzi. There is an urgent need for safe, effective, and accessible new treatments since the currently approved drugs have serious limitations. Drug development for Chagas disease has historically been hampered by the complexity of the disease, critical knowledge gaps, and lack of coordinated R&D efforts. This review covers some of the translational challenges associated with the progression of new chemical entities from preclinical to clinical phases of development, and discusses how recent technological advances might allow the research community to answer key questions relevant to the disease and to overcome hurdles in R&D for Chagas disease.

Key words:
Trypanosoma cruzi; animal model; in vitro assay; pharmacokinetic pharmacodynamic (PK/PD) relationship; dormancy; persisters

Authorship

Jadel M Kratz ⁺+ Corresponding authors: jkratz@dndi.org and ssosa@dndi.org

Drugs for Neglected Diseases initiative, Geneva, SwitzerlandDrugs for Neglected Diseases initiativeSwitzerlandGeneva, SwitzerlandDrugs for Neglected Diseases initiative, Geneva, Switzerland

http://orcid.org/0000-0002-7681-8234

Karolina R Gonçalves

Universidade de São Paulo, Instituto de Ciências Biomédicas, Departamento de Microbiologia, São Paulo, SP, BrasilUniversidade de São PauloBrazilSão Paulo, SP, BrazilUniversidade de São Paulo, Instituto de Ciências Biomédicas, Departamento de Microbiologia, São Paulo, SP, Brasil

Lavínia MD Romera

Carolina Borsoi Moraes

Universidade Federal de São Paulo, Departamento de Ciências Farmacêuticas, Diadema, SP, BrasilUniversidade Federal de São PauloBrazilDiadema, SP, BrazilUniversidade Federal de São Paulo, Departamento de Ciências Farmacêuticas, Diadema, SP, Brasil

Paula Bittencourt-Cunha

Universidade Federal de São Paulo, Departamento de Microbiologia, Imunologia e Parasitologia, São Paulo, SP, BrasilUniversidade Federal de São PauloBrazilSão Paulo, SP, BrazilUniversidade Federal de São Paulo, Departamento de Microbiologia, Imunologia e Parasitologia, São Paulo, SP, Brasil

Sergio Schenkman

Eric Chatelain

Drugs for Neglected Diseases initiative, Geneva, SwitzerlandDrugs for Neglected Diseases initiativeSwitzerlandGeneva, SwitzerlandDrugs for Neglected Diseases initiative, Geneva, Switzerland

Sergio Sosa-Estani ⁺+ Corresponding authors: jkratz@dndi.org and ssosa@dndi.org

Drugs for Neglected Diseases initiative, Geneva, SwitzerlandDrugs for Neglected Diseases initiativeSwitzerlandGeneva, SwitzerlandDrugs for Neglected Diseases initiative, Geneva, Switzerland

Epidemiology and Public Health Research Centre, CIESP-CONICET, Buenos Aires, ArgentinaEpidemiology and Public Health Research CentreArgentinaBuenos Aires, ArgentinaEpidemiology and Public Health Research Centre, CIESP-CONICET, Buenos Aires, Argentina

http://orcid.org/0000-0001-8701-5456

+ Corresponding authors: jkratz@dndi.org and ssosa@dndi.org

CBM, EC, JMK, SS and SS-E contributed to the conceptualisation and final review of this manuscript. All authors contributed to the writing and approved the final version of this manuscript. The authors declare no conflict of interest. Financial supporters had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

SCIMAGO INSTITUTIONS RANKINGS

Drugs for Neglected Diseases initiative, Geneva, SwitzerlandDrugs for Neglected Diseases initiativeSwitzerlandGeneva, SwitzerlandDrugs for Neglected Diseases initiative, Geneva, Switzerland

Figures

Figures (4)

Thumbnail

Fig. 1:
representation of Trypanosoma cruzi intracellular cycle in mammalian tissues. Trypomastigotes in blood interacts and invade mammalian cells forming a parasitophorous vacuole. The trypomastigotes exit the vacuole and transform into amastigote forms that start multiplying in the host cell cytosol (orange amastigotes). Following multiple rounds of division, amastigotes cease replication via cell cycle arrest (yellow to green amastigotes) and differentiate back into trypomastigotes that can egress and reinvade adjacent cells or circulate in the blood. The diagram also illustrates the existence of early cell cycle arrest in amastigotes (quiescent/dormant forms, light green) that can eventually differentiate back into trypomastigotes. Benznidazole (Bzn) and Posaconazole (Ps) inhibit primarily the intracellular multiplication of amastigotes.

Thumbnail

Fig. 2:
suggested screening cascade for the identification and progression of new chemical entities for Chagas disease. Assays used in different drug discovery stages (centre), with secondary profiling studies (right) and suggested progression criteria (left). HTS: high-throughput screening; HCS: high-content screening; IC₅₀: half maximal inhibitory concentration; MoA: mechanism of action; PK: pharmacokinetics; ADME: absorption, distribution, metabolism, excretion; BLI: bioluminescent; QD: quaque die (once a day); BID: bis in die (twice a day); PO: oral dosing; PK/PD: pharmacokinetic/pharmacodynamic relationships; Free C_min: free minimum plasma concentration; H2L: hit-to-lead phase; LO: lead optimisation phase.

Thumbnail

Fig. 3:
high content screening (HCS) for the discovery of anti-Trypanosoma cruzi compounds. (A) Schematic representation of a general HCS assay setup. Host cell lineage and T. cruzi strains of choice can vary significantly between laboratories and assays. Infected cells are exposed to compounds post-infection for a defined period of time and then antiparasitic activity is evaluated against intracellular amastigotes. Microplates are processed for image analysis. Highly active compounds will result in the (nearly complete) clearance of intracellular amastigotes. (B) Typical images of T. cruzi-infected cells treated with vehicle (left) and an efficacious concentration of benznidazole (right). Raw images are shown in red-stained host cell and parasite, and one key feature of HCS automated image analysis, amastigote segmentation and quantification, is shown in colored lines over grey-colored cells. While efficacious, benznidazole cannot often clear all intracellular amastigotes during short exposure times, and some amastigotes might remain after treatment (arrows).

Thumbnail

Fig. 4:
bioluminescent in vivo mouse Chagas disease model general scheme for compound efficacy assessment. N: imaging; dX: X days post-infection; t: round of immunosuppression X.

Fig. 1: representation of Trypanosoma cruzi intracellular cycle in mammalian tissues. Trypomastigotes in blood interacts and invade mammalian cells forming a parasitophorous vacuole. The trypomastigotes exit the vacuole and transform into amastigote forms that start multiplying in the host cell cytosol (orange amastigotes). Following multiple rounds of division, amastigotes cease replication via cell cycle arrest (yellow to green amastigotes) and differentiate back into trypomastigotes that can egress and reinvade adjacent cells or circulate in the blood. The diagram also illustrates the existence of early cell cycle arrest in amastigotes (quiescent/dormant forms, light green) that can eventually differentiate back into trypomastigotes. Benznidazole (Bzn) and Posaconazole (Ps) inhibit primarily the intracellular multiplication of amastigotes.

Fig. 2: suggested screening cascade for the identification and progression of new chemical entities for Chagas disease. Assays used in different drug discovery stages (centre), with secondary profiling studies (right) and suggested progression criteria (left). HTS: high-throughput screening; HCS: high-content screening; IC₅₀: half maximal inhibitory concentration; MoA: mechanism of action; PK: pharmacokinetics; ADME: absorption, distribution, metabolism, excretion; BLI: bioluminescent; QD: quaque die (once a day); BID: bis in die (twice a day); PO: oral dosing; PK/PD: pharmacokinetic/pharmacodynamic relationships; Free C_min: free minimum plasma concentration; H2L: hit-to-lead phase; LO: lead optimisation phase.

Fig. 3: high content screening (HCS) for the discovery of anti-Trypanosoma cruzi compounds. (A) Schematic representation of a general HCS assay setup. Host cell lineage and T. cruzi strains of choice can vary significantly between laboratories and assays. Infected cells are exposed to compounds post-infection for a defined period of time and then antiparasitic activity is evaluated against intracellular amastigotes. Microplates are processed for image analysis. Highly active compounds will result in the (nearly complete) clearance of intracellular amastigotes. (B) Typical images of T. cruzi-infected cells treated with vehicle (left) and an efficacious concentration of benznidazole (right). Raw images are shown in red-stained host cell and parasite, and one key feature of HCS automated image analysis, amastigote segmentation and quantification, is shown in colored lines over grey-colored cells. While efficacious, benznidazole cannot often clear all intracellular amastigotes during short exposure times, and some amastigotes might remain after treatment (arrows).

Fig. 4: bioluminescent in vivo mouse Chagas disease model general scheme for compound efficacy assessment. N: imaging; dX: X days post-infection; t: round of immunosuppression X.

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[1] + Corresponding authors: jkratz@dndi.org and ssosa@dndi.org