Drug Repurposing Against Toxoplasma gondii Through Comparative Analysis of Compound Potency, Selectivity, and Host-Cell Toxicity
DOI:
https://doi.org/10.69980/2wec8e33Keywords:
Toxoplasma gondii, drug repurposing, EC50, CC50, selectivity index, host-cell toxicityAbstract
Repurposing of drugs is a feasible approach to identify anti-Toxoplasma gondii candidates but potency is not enough if there is an overlap of activity with mammalian-cell toxicity or when activity is different between the different parasite stages. This study was a secondary comparative analysis of the open LOPAC screening dataset reported by Uddin et al. (2025) that screened 1280 pharmacologically active compounds and found 44 compounds that inhibited bradyzoites by more than 50%. The focus of the quantitative analysis was on the prioritized panel for which EC50 values were available for the tachyzoites (Tg68, ME49) and alkaline- and glutamine-induced bradyzoites (APTg68, APTg49) as well as CC50 values in HepG2 and differentiated THP-1 cells. Geometric means were used to summarize potency at each stage and overall; CC50 were used to evaluate the host cell safety; and minimum selectivity index across host cell models were used to represent robustness of selectivity. Of the main hits for repurposing, diphenyleneiodonium sulfate was the most potent overall (geometric-mean EC50 0.036 µM) and most selective (minimum SI 96). T0070907 was less potent (0.708 µM) and exhibited a good host-cell selectivity (SI 24–29). Brefeldin A, on the other hand, had a high apparent potency and a high cell-line dependent toxicity that resulted in a low SI of only 1. The analysis shows that prioritization of candidates differs significantly when the potency of the parasite and the toxicity to the host cells are considered simultaneously instead of using EC50 only. These results suggest a multi-parameter approach for the selection of anti-Toxoplasma confirmatory development compounds from the library of compounds that can be used for these purposes. Conservative cross-cell selectivity and consistency in development stage are used as a focus point and also a separation of compounds with consistent experimental windows from those that are only seemingly promising based on one positive assay. This will help increase transparency in decisions about repurposing in the early stages, and direct efficient allocation of confirmatory experimental resources. Toxoplasma gondii, Drug repurposing, EC50, CC50, Selectivity Index, Host-cell toxicity.
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