Emerging agents for the treatment of Chagas disease: what is in the preclinical and clinical development pipeline?

Martínez-Peinado, Nieves; Cortes-Serra, Núria; Losada, Irene; Alonso-Vega, Cristina; Urbina, Julio A.; Rodrı́guez, Ana; VandeBerg, John L.; Pinazo, María Jesús; Gascón, Joaquim; Alonso-Padilla, Julio

doi:10.1080/13543784.2020.1793955

Cited by 28 publications

(23 citation statements)

References 100 publications

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“…BNZ and NFX remain as the best possible Chagas disease treatments at the moment. It will be fundamental to determine whether alternative regimes currently under clinical evaluation manage to reduce their frequent adverse effects while maintaining (or increasing) efficacy [ 9 ]. Until then, efforts to try to identify a safe and highly effective therapy should continue.…”

Section: Discussionmentioning

confidence: 99%

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Anti-Trypanosoma cruzi Activity of Metabolism Modifier Compounds

Martínez-Peinado

Martori

Cortes-Serra

et al. 2021

IJMS

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Chagas disease is caused by the protozoan parasite Trypanosoma cruzi and affects over 6 million people worldwide. Development of new drugs to treat this disease remains a priority since those currently available have variable efficacy and frequent adverse effects, especially during the long regimens required for treating the chronic stage of the disease. T. cruzi modulates the host cell-metabolism to accommodate the cell cytosol into a favorable growth environment and acquire nutrients for its multiplication. In this study we evaluated the specific anti-T. cruzi activity of nine bio-energetic modulator compounds. Notably, we identified that 17-DMAG, which targets the ATP-binding site of heat shock protein 90 (Hsp90), has a very high (sub-micromolar range) selective inhibition of the parasite growth. This inhibitory effect was also highly potent (IC50 = 0.27 μmol L−1) against the amastigote intracellular replicative stage of the parasite. Moreover, molecular docking results suggest that 17-DMAG may bind T. cruzi Hsp90 homologue Hsp83 with good affinity. Evaluation in a mouse model of chronic T. cruzi infection did not show parasite growth inhibition, highlighting the difficulties encountered when going from in vitro assays onto preclinical drug developmental stages.

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Section: Discussionmentioning

confidence: 99%

“…Additionally, drug resistance has been observed in some discrete typing units (DTUs) [ 8 ], and no vaccine or chemo-prophylactic agents are available. Therefore, identification of safer and more efficacious drugs to treat the chronic stage of the infection is urgently needed [ 9 ].…”

Section: Introductionmentioning

confidence: 99%

Anti-Trypanosoma cruzi Activity of Metabolism Modifier Compounds

Martínez-Peinado

Martori

Cortes-Serra

et al. 2021

IJMS

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“…In the last few years, several efforts have been directed towards the identification of new active compounds against T. cruzi [11][12][13]. Among those drug discovery approaches, repositioning of already licensed drugs should also be contemplated, as it stands out as an attractive fast-track and low-cost strategy [14].…”

Section: Introductionmentioning

confidence: 99%

Identification of Trypanosoma cruzi Growth Inhibitors with Activity In Vivo within a Collection of Licensed Drugs

et al. 2021

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Chagas disease, caused by the parasite Trypanosoma cruzi (T. cruzi), affects more than six million people worldwide, with its greatest burden in Latin America. Available treatments present frequent toxicity and variable efficacy at the chronic phase of the infection, when the disease is usually diagnosed. Hence, development of new therapeutic strategies is urgent. Repositioning of licensed drugs stands as an attractive fast-track low-cost approach for the identification of safer and more effective chemotherapies. With this purpose we screened 32 licensed drugs for different indications against T. cruzi. We used a primary in vitro assay of Vero cells infection by T. cruzi. Five drugs showed potent activity rates against it (IC50 < 4 µmol L−1), which were also specific (selectivity index > 15) with respect to host cells. T. cruzi inhibitory activity of four of them was confirmed by a secondary anti-parasitic assay based on NIH-3T3 cells. Then, we assessed toxicity to human HepG2 cells and anti-amastigote specific activity of those drugs progressed. Ultimately, atovaquone-proguanil, miltefosine, and verapamil were tested in a mouse model of acute T. cruzi infection. Miltefosine performance in vitro and in vivo encourages further investigating its use against T. cruzi.

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“…According to Thompson et al, the phenotypic screening of libraries with several compounds is still considered the best strategy to identify new leads or starting points [7]. Moreover, the discovery of new drugs for Chagas disease need collaborative networks involving academia, pharmaceutical companies, government organs and entities such as DNDi (Drugs for Neglected Diseases initiative), all of them contributing for substantial advances where actions must be as synergistic as possible in order to support the translation of academic research into available drugs [9,10]. Many of the methods used in the field of drug discovery are powerful and can offer important information about interactions and functions; however, they require access to the 3D structure of the protein in question [11].…”

Section: Introductionmentioning

confidence: 99%

“…The drug discovery process for Chagas disease has been ongoing with thousands of compounds tested annually before finding a promising candidate. High throughput screening (HTS) campaigns, which represent an important approach to identify new sets of leads for treatment, have been carried out [ 10 ]. The DNDi is developing a portfolio of early hits and lead series with collections of natural products and synthetic compounds to find new drug candidates for Chagas disease.…”

Section: Introductionmentioning

confidence: 99%

Chagas Disease: Perspectives on the Past and Present and Challenges in Drug Discovery

et al. 2020

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Chagas disease still has no effective treatment option for all of its phases despite being discovered more than 100 years ago. The development of commercial drugs has been stagnating since the 1960s, a fact that sheds light on the question of how drug discovery research has progressed and taken advantage of technological advances. Could it be that technological advances have not yet been sufficient to resolve this issue or is there a lack of protocol, validation and standardization of the data generated by different research teams? This work presents an overview of commercial drugs and those that have been evaluated in studies and clinical trials so far. A brief review is made of recent target-based and phenotypic studies based on the search for molecules with anti-Trypanosoma cruzi action. It also discusses how proteochemometric (PCM) modeling and microcrystal electron diffraction (MicroED) can help in the case of the lack of a 3D protein structure; more specifically, Trypanosoma cruzi carbonic anhydrase.

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Emerging agents for the treatment of Chagas disease: what is in the preclinical and clinical development pipeline?

Cited by 28 publications

References 100 publications

Anti-Trypanosoma cruzi Activity of Metabolism Modifier Compounds

Anti-Trypanosoma cruzi Activity of Metabolism Modifier Compounds

Identification of Trypanosoma cruzi Growth Inhibitors with Activity In Vivo within a Collection of Licensed Drugs

Chagas Disease: Perspectives on the Past and Present and Challenges in Drug Discovery

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