Publication
Title
Screening of the Pathogen Box for inhibitors with dual efficacy against Giardia lamblia and Cryptosporidium parvum
Author
Abstract
There is need for a more efficient cell-based assay amenable to high-throughput drug screening against Giardia lamblia. Here, we report the development of a screening method utilizing G. lamblia engineered to express red-shifted firefly luciferase. Parasite growth and replication were quantified using D-luciferin as a substrate in a bioluminescent read-out plateform. This assay was validated for reproducibility and reliability against the Medicines for Malaria Venture (MMV) Pathogen Box compounds. For G. lamblia, forty-three compounds showed >= 75% inhibition of parasite growth in the initial screen (16 mu M), with fifteen showing >= 95% inhibition. The Pathogen Box was also screened against Nanoluciferase expressing (Nluc) C. parvum, yielding 85 compounds with >= 75% parasite growth inhibition at 10 mu M, with six showing >= 95% inhibition. A representative set of seven compounds with activity against both parasites were further analyzed to determine the effective concentration that causes 50% growth inhibition (EC50) and cytotoxicity against mammalian HepG2 cells. Four of the seven compounds were previously known to be effective in treating either Giardia or Cryptosporidium. The remaining three shared no obvious chemical similarity with any previously characterized anti-parasite diarrheal drugs and offer new medicinal chemistry opportunities for therapeutic development. These results suggest that the bioluminescent assays are suitable for large-scale screening of chemical libraries against both C. parvum and G. lamblia.
Language
English
Source (journal)
PLoS neglected tropical diseases
Publication
2018
ISSN
1935-2727
1935-2735
Volume/pages
12 :8 (2018) , 16 p.
Article Reference
e0006673
ISI
000443381000028
Pubmed ID
30080847
Medium
E-only publicatie
Full text (Publisher's DOI)
Full text (open access)
UAntwerpen
Publication type
Subject
Affiliation
Publications with a UAntwerp address
External links
Web of Science
Record
Identification
Creation 08.10.2018
Last edited 25.08.2021
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