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Deregulation of Acanthamoeba castellanii steroidogenesis is amoebicidal and protects cultured corneal cells from Ac attack
Author(s) -
Vanderloop Boden H.,
Thomas Crista D.,
Zhou Wenxu,
Gillespie Amelia A.,
Singha Ujjal,
Chaudhuri Minu,
Neelam Sudha,
Niederkorn Jerry,
Nes William David
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2019.33.1_supplement.634.15
Subject(s) - sterol , amoeba (genus) , biology , acanthamoeba , biosynthesis , microbiology and biotechnology , enzyme , pharmacology , biochemistry , cholesterol
Human infections by amoeba represent rare diseases, yet they are an emerging health problem that can develop into rapid death, as in cases involving the spinal cord or amoeba that penetrate the brain. Our recent papers highlighted in J. Lipid Res , 2017 and ASBMB Today magazine, 2018 focus on development of new sterol methyltransferase (SMT) inhibitors to prevent steroidogenesis in the parasitic amoeba Acanthamoeba castellanii (Ac). Now we show, Ac cultured on unexplored sterol C24‐methyltransferase (SMT) inhibitors 25‐azalanosterol and 25‐thialanosterol iodine salt are highly potent anti‐amoeba drugs exhibiting IC 50 25 nM and 15 nM, respectively and a minimum amoebicidal concentration of 1 μM. Both analogs inhibited the cloned 24‐ Ac SMT and 28‐ Ac SMT yielding K i values of 13 nM/37nM and 9nM/16nM, respectively and blocked Ac steroidogenesis at the target enzyme. Against human epithelial kidney cell growth these drugs had no effect to 40 μM or effected cholesterol biosynthesis (selective index greater than 10 3 ); in mice at 50 mg/kg, 3 H‐analog could rapidly cross the blood brain barrier with minimal effect on liver cholesterol biosynthesis. Against human corneal epithelial cultures infected with Ac, the drugs protected the eye at doses of 500 nM. These new amoeba sterol biosynthesis inhibitors are currently under investigation for their therapeutic potential. Support or Funding Information This research was funded through a grant from the National Institutes of Health. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .