Novel and selective inactivators of Triosephosphate isomerase with anti-trematode activity

Ferraro, Florencia; Corvo, Ileana; Bergalli, Lucia; Ilarraz, Andrea; Cabrera, Mauricio; Gil, J.; Susuki, Brian M.; Caffrey, Conor R.; Timson, David J.; Robert, Xavier; Guillon, Christophe; Freire, Teresa; Álvarez, Guzmán

doi:10.1038/s41598-020-59460-y

Cited by 15 publications

(6 citation statements)

References 57 publications

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“…A selective inhibitor of Trypanosoma cruzi triosephosphate isomerase dramatically reduced parasites in the blood of experimentally infected mice and greatly enhanced their survival rate ( Aguilera et al, 2016 ). Selective Fasciola hepatica triosephosphate isomerase inactivators could kill the juvenile form of F. hepatica in low concentration and showed low host toxicity ( Ferraro et al, 2020 ). In addition to its effect on energy production, inhibition of triosephosphate isomerase results in accumulation of dihydroxyacetone phosphate or D-glyceraldehyde 3-phosphate, which can be cytotoxic ( Han and Weiss, 2018 ).…”

Section: Other Promising Therapeutic Targetsmentioning

confidence: 99%

Current Therapy and Therapeutic Targets for Microsporidiosis

et al. 2022

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Microsporidia are obligate intracellular, spore-forming parasitic fungi which are grouped with the Cryptomycota. They are both opportunistic pathogens in humans and emerging veterinary pathogens. In humans, they cause chronic diarrhea in immune-compromised patients and infection is associated with increased mortality. Besides their role in pébrine in sericulture, which was described in 1865, the prevalence and severity of microsporidiosis in beekeeping and aquaculture has increased markedly in recent decades. Therapy for these pathogens in medicine, veterinary, and agriculture has become a recent focus of attention. Currently, there are only a few commercially available antimicrosporidial drugs. New therapeutic agents are needed for these infections and this is an active area of investigation. In this article we provide a comprehensive summary of the current as well as several promising new agents for the treatment of microsporidiosis including: albendazole, fumagillin, nikkomycin, orlistat, synthetic polyamines, and quinolones. Therapeutic targets which could be utilized for the design of new drugs are also discussed including: tubulin, type 2 methionine aminopeptidase, polyamines, chitin synthases, topoisomerase IV, triosephosphate isomerase, and lipase. We also summarize reports on the utility of complementary and alternative medicine strategies including herbal extracts, propolis, and probiotics. This review should help facilitate drug development for combating microsporidiosis.

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Section: Other Promising Therapeutic Targetsmentioning

confidence: 99%

Current Therapy and Therapeutic Targets for Microsporidiosis

et al. 2022

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“…The IC 50 was defined as the drug concentration at which 50% of the cells were viable, relative to the control (no drug added), and was determined by analysis using OriginLab 8.5 Corporation, Northampton, MA, USA, sigmoidal regression (% of viable cells compared to the logarithm of the compound concentration). The tests were performed in triplicate in two independent experiments [32].…”

Section: Nonspecific Cytotoxicity 241 Cytotoxicity Assay On Murine Ma...mentioning

confidence: 99%

Phenotypic and Target-Directed Screening Yields New Acaricidal Alternatives for the Control of Ticks

et al. 2022

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Rhipicephalus microplus, the “common cattle tick”, is the most important ectoparasite in livestock worldwide due to the economic and health losses it produces. This tick is a vector for pathogens of several tick-borne diseases. In Latin American countries, damages reach approximately USD 500 million annually due to tick infections, as well as tick-borne diseases. Currently, resistant populations for every chemical group of acaricides have been reported, posing a serious problem for tick control. This study aims to find new alternatives for controlling resistant ticks with compounds derived from small synthetic organic molecules and natural origins. Using BME26 embryonic cells, we performed phenotypic screening of 44 natural extracts from 10 Mexican plants used in traditional medicine, and 33 compounds selected from our chemical collection. We found 10 extracts and 13 compounds that inhibited cell growth by 50% at 50 µg/mL and 100 µM, respectively; the dose-response profile of two of them was characterized, and these compounds were assayed in vitro against different life stages of Rhipicephalus microplus. We also performed a target-directed screening of the activity of triosephosphate isomerase, using 86 compounds selected from our chemical collection. In this collection, we found the most potent and selective inhibitor of tick triosephosphate isomerase reported until now. Two other compounds had a potent acaricidal effect in vitro using adults and larvae when compared with other acaricides such as ivermectin and Amitraz. Those compounds were also selective to the ticks compared with the cytotoxicity in mammalian cells like macrophages or bovine spermatozoids. They also had a good toxicological profile, resulting in promising acaricidal compounds for tick control in cattle raising.

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“…The effective compound concentration that inhibits cell growth by 50% (EC 50 ) was established using OriginLab8.5 ® sigmoidal. All assays were performed in triplicate [35].…”

Section: Nonspecific In Vitro Cytotoxicity In Mammalian Cellsmentioning

confidence: 99%

Preclinical Studies in Anti-Trypanosomatidae Drug Development

et al. 2021

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The trypanosomatid parasites Trypanosoma brucei, Trypanosoma cruzi and Leishmania are the causative agents of human African trypanosomiasis, Chagas Disease and Leishmaniasis, respectively. These infections primarily affect poor, rural communities in the developing world, and are responsible for trapping sufferers and their families in a disease/poverty cycle. The development of new chemotherapies is a priority given that existing drug treatments are problematic. In our search for novel anti-trypanosomatid agents, we assess the growth-inhibitory properties of >450 compounds from in-house and/or “Pathogen Box” (PBox) libraries against L. infantum, L. amazonensis, L.braziliensis, T. cruzi and T. brucei and evaluate the toxicities of the most promising agents towards murine macrophages. Screens using the in-house series identified 17 structures with activity against and selective toward Leishmania: Compounds displayed 50% inhibitory concentrations between 0.09 and 25 μM and had selectivity index values >10. For the PBox library, ~20% of chemicals exhibited anti-parasitic properties including five structures whose activity against L. infantum had not been reported before. These five compounds displayed no toxicity towards murine macrophages over the range tested with three being active in an in vivo murine model of the cutaneous disease, with 100% survival of infected animals. Additionally, the oral combination of three of them in the in vivo Chagas disease murine model demonstrated full control of the parasitemia. Interestingly, phenotyping revealed that the reference strain responds differently to the five PBox-derived chemicals relative to parasites isolated from a dog. Together, our data identified one drug candidate that displays activity against Leishmania and other Trypanosomatidae in vitro and in vivo, while exhibiting low toxicity to cultured mammalian cells and low in vivo acute toxicity.

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Novel and selective inactivators of Triosephosphate isomerase with anti-trematode activity

Cited by 15 publications

References 57 publications

Current Therapy and Therapeutic Targets for Microsporidiosis

Current Therapy and Therapeutic Targets for Microsporidiosis

Phenotypic and Target-Directed Screening Yields New Acaricidal Alternatives for the Control of Ticks

Preclinical Studies in Anti-Trypanosomatidae Drug Development

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