Repurposing the Medicines for Malaria Venture’s COVID Box to discover potent inhibitors of Toxoplasma gondii, and in vivo efficacy evaluation of almitrine bismesylate (MMV1804175) in chronically infected mice.

Publication date: May 11, 2023

Toxoplasmosis, caused by the obligate intracellular parasite Toxoplasma gondii, affects about one-third of the world’s population and can cause severe congenital, neurological and ocular issues. Current treatment options are limited, and there are no human vaccines available to prevent transmission. Drug repurposing has been effective in identifying anti-T. gondii drugs. In this study, the screening of the COVID Box, a compilation of 160 compounds provided by the “Medicines for Malaria Venture” organization, was conducted to explore its potential for repurposing drugs to combat toxoplasmosis. The objective of the present work was to evaluate the compounds’ ability to inhibit T. gondii tachyzoite growth, assess their cytotoxicity against human cells, examine their absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties, and investigate the potential of one candidate drug through an experimental chronic model of toxoplasmosis. Early screening identified 29 compounds that could inhibit T. gondii survival by over 80% while keeping human cell survival up to 50% at a concentration of 1 μM. The Half Effective Concentrations (EC50) of these compounds ranged from 0. 04 to 0. 92 μM, while the Half Cytotoxic Concentrations (CC50) ranged from 2. 48 to over 50 μM. Almitrine was chosen for further evaluation due to its favorable characteristics, including anti-T. gondii activity at nanomolar concentrations, low cytotoxicity, and ADMET properties. Administering almitrine bismesylate (Vectarion(R)) orally at dose of 25 mg/kg/day for ten consecutive days resulted in a statistically significant (p < 0. 001) reduction in parasite burden in the brains of mice chronically infected with T. gondii (ME49 strain). This was determined by quantifying the RNA of living parasites using real-time PCR. The presented results suggest that almitrine may be a promising drug candidate for additional experimental studies on toxoplasmosis and provide further evidence of the potential of the MMV collections as a valuable source of drugs to be repositioned for infectious diseases.

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Concepts Keywords
Mice Almitrine
Mmv1804175 Box
Pcr Compounds
Vaccines Concentrations
Valuable Covid


Type Source Name
disease MESH Malaria
pathway KEGG Malaria
drug DRUGBANK Almitrine
disease MESH Toxoplasmosis
pathway KEGG Toxoplasmosis
disease IDO parasite
disease VO population
disease VO effective
disease VO organization
pathway REACTOME Metabolism
disease IDO cell
disease VO dose
drug DRUGBANK Pentaerythritol tetranitrate
disease VO time
disease MESH infectious diseases
drug DRUGBANK Coenzyme M
disease MESH hypersensitivity
drug DRUGBANK Pyrimethamine
disease MESH bacterial infections
disease IDO pathogen
drug DRUGBANK Dimethyl sulfoxide
drug DRUGBANK Phosphate ion
drug DRUGBANK Sodium lauryl sulfate
drug DRUGBANK L-Glutamine
drug DRUGBANK Gentamicin
disease IDO assay
drug DRUGBANK Magnesium sulfate
disease VO viability
disease VO USA
disease IDO facility
drug DRUGBANK Water
disease MESH infection
disease VO protocol
disease MESH Chronic infection
disease VO intraperitoneal injection
disease MESH cysts
disease VO injection
disease MESH apathy
disease MESH alopecia
disease VO volume
disease VO organ
drug DRUGBANK Potassium Chloride
disease VO Gag
drug DRUGBANK 5-amino-1 3 4-thiadiazole-2-thiol
drug DRUGBANK Thiocolchicoside
drug DRUGBANK Timonacic
disease VO TTC
drug DRUGBANK Ademetionine
disease VO ANOVA
disease VO Glycoprotein
drug DRUGBANK Abemaciclib
drug DRUGBANK Itraconazole
drug DRUGBANK Niclosamide
drug DRUGBANK Regorafenib
drug DRUGBANK Tioguanine
drug DRUGBANK Ciclosporin
drug DRUGBANK Sorafenib
drug DRUGBANK Manidipine
drug DRUGBANK Tetrandrine
drug DRUGBANK Fluspirilene
drug DRUGBANK Tetracycline
drug DRUGBANK Toremifene
drug DRUGBANK Sirolimus
drug DRUGBANK Anidulafungin
drug DRUGBANK Thiethylperazine
drug DRUGBANK Merimepodib
drug DRUGBANK Nebivolol
drug DRUGBANK Pimozide
disease MESH COVID 19
disease IDO site
disease MESH drug interactions
disease VO oral route
disease MESH COPD
disease MESH polyneuropathy
disease VO Tox
drug DRUGBANK Atovaquone

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