Journal
ACS INFECTIOUS DISEASES
Volume 5, Issue 12, Pages 2029-2038Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsinfecdis.9b00227
Keywords
drug discovery; homology modeling; Naegleria fowleri; primary amoebic meningoencephalitis; virtual ligand screen
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Funding
- UCSD Academic Senate bridge fund program [1KL2TR001444, R21A1133394]
- NIH
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Naegleria fowleri is a free-living amoeba causing primary amoebic meningoencephalitis, a rapid-onset brain infection in humans with over 97% mortality rate. Despite some progress in the treatment of the disease, there is no single, proven, evidence-based treatment with a high probability of cure. Here we report the chemical library screening and experimental identification of four new compounds with amoebicidal effects against N. fowleri. The chemical library was screened by molecular docking against a homology model of sterol Delta 8-Delta 7 isomerase (NfERG2). Thirty top-ranking hits were then tested in a cell-based assay for antiproliferative/amoebicidal activities. Eight chemicals exhibited nearly 100% inhibition of N. fowleri at 50 mu M, with the EC50 values ranging from 6 to 25 mu M. A cell toxicity assay using human HEK-293 cells was also performed. Four of the compounds preferentially kill amoeba cells with no apparent human cell toxicities. These compounds fall into two distinct chemical scaffolds with druglike properties.
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