High-throughput phenotypic screen identifies a new family of potent anti-amoebic compounds
Issued Date
2023-05-01
Resource Type
eISSN
19326203
Scopus ID
2-s2.0-85159564156
Pubmed ID
37159460
Journal Title
PLoS ONE
Volume
18
Issue
5 May
Rights Holder(s)
SCOPUS
Bibliographic Citation
PLoS ONE Vol.18 No.5 May (2023)
Suggested Citation
Sauvey C., Meewan I., Ehrenkaufer G., Blevitt J., Jackson P., Abagyan R. High-throughput phenotypic screen identifies a new family of potent anti-amoebic compounds. PLoS ONE Vol.18 No.5 May (2023). doi:10.1371/journal.pone.0280232 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/82877
Title
High-throughput phenotypic screen identifies a new family of potent anti-amoebic compounds
Other Contributor(s)
Abstract
Entamoeba histolytica is a disease-causing parasitic amoeba which affects an estimated 50 million people worldwide, particularly in socioeconomically vulnerable populations experiencing water sanitation issues. Infection with E. histolytica is referred to as amoebiasis, and can cause symptoms such as colitis, dysentery, and even death in extreme cases. Drugs exist that are capable of killing this parasite, but they are hampered by downsides such as significant adverse effects at therapeutic concentrations, issues with patient compliance, the need for additional drugs to kill the transmissible cyst stage, and potential development of resistance. Past screens of small and medium sized chemical libraries have yielded anti-amoebic candidates, thus rendering high-throughput screening a promising direction for new drug discovery in this area. In this study, we screened a curated 81,664 compound library from Janssen pharmaceuticals against E. histolytica trophozoites in vitro, and from it identified a highly potent new inhibitor compound. The best compound in this series, JNJ001, showed excellent inhibition activity against E. histolytica trophozoites with EC50 values at 0.29 μM, which is better than the current approved treatment, metronidazole. Further experimentation confirmed the activity of this compound, as well as that of several structurally related compounds, originating from both the Janssen Jump-stARter library, and from chemical vendors, thus highlighting a new structure-activity relationship (SAR). In addition, we confirmed that the compound inhibited E. histolytica survival as rapidly as the current standard of care and inhibited transmissible cysts of the related model organism Entamoeba invadens. Together these results constitute the discovery of a novel class of chemicals with favorable in vitro pharmacological properties. The discovery may lead to an improved therapy against this parasite and in all of its life stages.
