Phenothiazine Radicals Inactivate Trypanosoma cruzi Dihydrolipoamide Dehydrogenase: Enzyme Protection by Radical Scavengers

Gutiérrez-Correa, José; Krauth‐Siegel, R. Luise; Stoppani, A. O. M.

doi:10.1080/1071576021000046622

Cited by 15 publications

(10 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Berberine, ipecac syrup, disulfiram, methylene blue hydrate, promethazine hydrochloride, perphenazine, promazine hydrochloride, and triflupromazine have all previously been reported to inhibit growth in T. brucei and our results agree with those previously published reports [25][26][27][28][29] (S1 Table, S2 Table). Several other drugs, including nitrofurazone, aminacrine, clemastine fumarate, bepridil hydrochloride, amiodarone hydrochloride, prochlorperazine dimaleate, protriptyline hydrochloride, fluoxetine hydrochloride, apomorphine hydrochloride, and proadifen hydrochloride have been shown to inhibit growth in T. cruzi [27,[30][31][32][33][34][35][36][37][38]. Finally, cyproheptadine hydrochloride was shown to inhibit growth in T. evansi (S1 Table) [39].…”

Section: Identification Of In Vitro Inhibitors For T Brucei Growthsupporting

confidence: 93%

Identification of clinically approved small molecules that inhibit growth and affect transcript levels of developmentally regulated genes in the African trypanosome

et al. 2020

View full text Add to dashboard Cite

Trypanosoma brucei are unicellular parasites endemic to Sub-Saharan Africa that cause fatal disease in humans and animals. Infection with these parasites is caused by the bite of the tsetse fly vector, and parasites living extracellularly in the blood of infected animals evade the host immune system through antigenic variation. Existing drugs for Human and Animal African Trypanosomiasis are difficult to administer and can have serious side effects. Resistance to some drugs is also increasing, creating an urgent need for alternative trypanosomiasis therapeutics. We screened a library of 1,585 U.S. or foreign-approved drugs and identified 154 compounds that inhibit trypanosome growth. As all of these compounds have already undergone testing for human toxicity, they represent good candidates for repurposing as trypanosome therapeutics. In addition to identifying drugs that inhibit trypanosome growth, we wished to identify small molecules that can induce bloodstream form parasites to differentiate into forms adapted for the insect vector. These insect stage parasites lack the immune evasion mechanisms prevalent in bloodstream forms, making them vulnerable to the host immune system. To identify drugs that increase transcript levels of an invariant, insect-stage specific surface protein called procyclin, we engineered bloodstream reporter parasites that express Green Fluorescent Protein (GFP) following induction or stabilization of the procyclin transcript. Using these bloodstream reporter strains in combination with automated flow cytometry, we identified eflornithine, spironolactone, and phenothiazine as small molecules that increase abundance of procyclin transcript. Both eflornithine and spironolactone also affect transcript levels for a subset of differentiation associated genes. While we failed to identify compounds that increase levels of procyclin protein on the cell surface, this study is proof of principle that these fluorescent reporter parasites represent a useful tool for future small molecule or genetic screens aimed at identifying molecules or processes that initiate remodeling of the parasite surface during life cycle stage transitions.

show abstract

Section: Identification Of In Vitro Inhibitors For T Brucei Growthsupporting

confidence: 93%

Identification of clinically approved small molecules that inhibit growth and affect transcript levels of developmentally regulated genes in the African trypanosome

et al. 2020

View full text Add to dashboard Cite

show abstract

“…Reacting with GSH, CPZ cation radical leads to the formation of GSH thiol radical cation of CPZ, which is responsible for both pharmacological efficacy and toxic effects of this drug. Inevitably, depleted GSH storage makes antioxidative defense system more fragile, what means that this drug can initiate OS in the brain 16 .…”

Section: Discussionmentioning

confidence: 99%

“…•sequestration 16 . Increased SOD activities that are registered in both M and in S group are probably induced by the increased production of ROS and CPZ cation radical, consequently.…”

Section: Discussionmentioning

confidence: 99%

Oxidative stress induced by chlorpromazine in patients treated and acutely poisoned with the drug

Dejanović¹,

Vukovic-Dejanovic²,

Stevanović

et al. 2016

VSP

View full text Add to dashboard Cite

show abstract

“…We binned each drug into four categories: highly inhibitory, inhibitory, slightly inhibitory, and not inhibitory ( Table, S3 Table). Several other drugs, including nitrofurazone, aminacrine, clemastine fumarate, bepridil hydrochloride, amiodarone hydrochloride, prochlorperazine dimaleate, protriptyline hydrochloride, fluoxetine hydrochloride, apomorphine hydrochloride, and proadifen hydrochloride have been shown to inhibit growth in T. cruzi (33,(36)(37)(38)(39)(40)(41)(42)(43)(44). Finally, cyproheptadine hydrochloride was shown to inhibit growth in T. evansi (S2 Table) (45).…”

Section: Identification Of In Vitro Inhibitors For T Brucei Growthmentioning

confidence: 99%

Identification of clinically approved small molecules that inhibit growth and promote surface remodeling in the African trypanosome

Walsh

Naudzius

Diaz

et al. 2019

Preprint

View full text Add to dashboard Cite

Trypanosoma brucei are unicellular parasites endemic to Sub-Saharan Africa that cause fatal disease in humans and animals. Infection with these parasites is caused by the bite of the tsetse fly vector, and parasites living extracellularly in the blood of infected animals evade the host immune system through antigenic variation. Existing drugs for Human and Animal African Trypanosomiasis are difficult to administer and can have serious side effects. Resistance to some drugs is also increasing, creating an urgent need for alternative trypanosomiasis therapeutics. In addition to identifying drugs that inhibit trypanosome growth, we wish to identify small molecules that can induce bloodstream form parasites to differentiate into forms adapted for the insect vector. These insect stage parasites do not vary proteins on their cell surface, making them vulnerable to the host immune system. To identify drugs that trigger differentiation of the parasite from bloodstream to insect stages, we engineered bloodstream reporter parasites that express Green Fluorescent Protein (GFP) following induction of the invariant insect-stage specific procyclin transcript. Using these bloodstream reporter strains in combination with high-throughput flow cytometry, we screened a library of 1,585 U.S. or foreignapproved drugs and identified eflornithine, spironolactone, and phenothiazine as small molecules that induce transcription of procylin. Both eflornithine and spironolactone also affect transcript levels for a subset of differentiation associated genes. We further identified 154 compounds that inhibit trypanosome growth. As all of these compounds have already undergone testing for human toxicity, they represent good candidates for repurposing as trypanosome therapeutics. Finally, this study is proof of principle that fluorescent reporters are a useful tool for small molecule or genetic screens aimed at identifying molecules or processes that initiate remodeling of the parasite surface during life cycle stage transitions. Author SummaryAfrican trypanosomes are unicellular parasites that infect humans and animals, causing a fatal disease known as sleeping sickness in humans and nagana in cattle. These diseases impose a severe economic burden for people living in Sub-Saharan Africa, where parasites are transmitted to humans and animals through the bite of the tsetse fly. Parasites living outside cells in humans and animals are attacked by the antibodies of the host immune system, but they can evade this attack by varying the proteins on their cell surface. In contrast, because flies do not have an antibody-mediated immune response, parasites living in flies do not vary the proteins on their cell surface. In this study, we performed a small molecule screen to identify compounds that might force bloodstream parasites to move forward in their life cycle to become more similar to parasites living in flies, causing them to express a protein on their cell surface that does not vary. This invariant protein on the surface of bloodstream parasites ...

show abstract

Phenothiazine Radicals Inactivate Trypanosoma cruzi Dihydrolipoamide Dehydrogenase: Enzyme Protection by Radical Scavengers

Cited by 15 publications

References 36 publications

Identification of clinically approved small molecules that inhibit growth and affect transcript levels of developmentally regulated genes in the African trypanosome

Identification of clinically approved small molecules that inhibit growth and affect transcript levels of developmentally regulated genes in the African trypanosome

Oxidative stress induced by chlorpromazine in patients treated and acutely poisoned with the drug

Identification of clinically approved small molecules that inhibit growth and promote surface remodeling in the African trypanosome

Contact Info

Product

Resources

About