title: Repurposing auranofin as a lead candidate for treatment of lymphatic filariasis and onchocerciasis.
abstract: Two major human diseases caused by filariid nematodes are onchocerciasis, or river blindness, and lymphatic filariasis, which can lead to elephantiasis. The drugs ivermectin, diethylcarbamazine (DEC), and albendazole are used in control programs for these diseases, but are mainly effective against the microfilarial stage and have minimal or no effect on adult worms. Adult Onchocerca volvulus and Brugia malayi worms (macrofilariae) can live for up to 15 years, reproducing and allowing the infection to persist in a population. Therefore, to support control or elimination of these two diseases, effective macrofilaricidal drugs are necessary, in addition to current drugs. In an effort to identify macrofilaricidal drugs, we screened an FDA-approved library with adult worms of Brugia spp. and Onchocerca ochengi, third-stage larvae (L3s) of Onchocerca volvulus, and the microfilariae of both O. ochengi and Loa loa. We found that auranofin, a gold-containing drug used for rheumatoid arthritis, was effective in vitro in killing both Brugia spp. and O. ochengi adult worms and in inhibiting the molting of L3s of O. volvulus with IC50 values in the low micromolar to nanomolar range. Auranofin had an approximately 43-fold higher IC50 against the microfilariae of L. loa compared with the IC50 for adult female O. ochengi, which may be beneficial if used in areas where Onchocerca and Brugia are co-endemic with L. loa, to prevent severe adverse reactions to the drug-induced death of L. loa microfilariae. Further testing indicated that auranofin is also effective in reducing Brugia adult worm burden in infected gerbils and that auranofin may be targeting the thioredoxin reductase in this nematode.
authors.affiliation: Center for Discovery and Innovation in Parasitic Diseases, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Christina A
authors.initials: CA
authors.lastname: Bulman
authors.affiliation: Center for Discovery and Innovation in Parasitic Diseases, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Chelsea M
authors.initials: CM
authors.lastname: Bidlow
authors.affiliation: Lindsley F. Kimball Research Institute, New York Blood Center, New York, New York, United States of America.
authors.forename: Sara
authors.initials: S
authors.lastname: Lustigman
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Buea, Buea, SW Region, Cameroon.
authors.forename: Fidelis
authors.initials: F
authors.lastname: Cho-Ngwa
authors.affiliation: Department of Immunology and Microbiology, Rush University Medical Center, Chicago, Illinois, United States of America.
authors.forename: David
authors.initials: D
authors.lastname: Williams
authors.affiliation: Center for Discovery and Innovation in Parasitic Diseases, University of California San Francisco, San Francisco, California, United States of America; Department of Chemistry, San Jose State University, San Jose, California, United States of America.
authors.forename: Alberto A
authors.initials: AA
authors.lastname: Rascón
authors.affiliation: Lindsley F. Kimball Research Institute, New York Blood Center, New York, New York, United States of America.
authors.forename: Nancy
authors.initials: N
authors.lastname: Tricoche
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Buea, Buea, SW Region, Cameroon.
authors.forename: Moses
authors.initials: M
authors.lastname: Samje
authors.affiliation: Lindsley F. Kimball Research Institute, New York Blood Center, New York, New York, United States of America.
authors.forename: Aaron
authors.initials: A
authors.lastname: Bell
authors.affiliation: Center for Discovery and Innovation in Parasitic Diseases, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Brian
authors.initials: B
authors.lastname: Suzuki
authors.affiliation: Center for Discovery and Innovation in Parasitic Diseases, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: K C
authors.initials: KC
authors.lastname: Lim
authors.affiliation: FilariaTech, Athens, Georgia, United States of America.
authors.forename: Nonglak
authors.initials: N
authors.lastname: Supakorndej
authors.affiliation: Department of Infectious Diseases, University of Georgia, Athens, Georgia, United States of America.
authors.forename: Prasit
authors.initials: P
authors.lastname: Supakorndej
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Alan R
authors.initials: AR
authors.lastname: Wolfe
authors.affiliation: UCSF Mass Spectrometry Facility, Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Giselle M
authors.initials: GM
authors.lastname: Knudsen
authors.affiliation: Small Molecule Discovery Center, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Steven
authors.initials: S
authors.lastname: Chen
authors.affiliation: Small Molecule Discovery Center, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Chris
authors.initials: C
authors.lastname: Wilson
authors.affiliation: Small Molecule Discovery Center, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Kean-Hooi
authors.initials: KH
authors.lastname: Ang
authors.affiliation: Small Molecule Discovery Center, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Michelle
authors.initials: M
authors.lastname: Arkin
authors.affiliation: Center for Discovery and Innovation in Parasitic Diseases, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Jiri
authors.initials: J
authors.lastname: Gut
authors.affiliation: Center for Discovery and Innovation in Parasitic Diseases, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Chris
authors.initials: C
authors.lastname: Franklin
authors.affiliation: Case Western Reserve University School of Medicine, Cleveland, Ohio, United States of America.
authors.forename: Chris
authors.initials: C
authors.lastname: Marcellino
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, San Diego, California, United States of America.
authors.forename: James H
authors.initials: JH
authors.lastname: McKerrow
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, San Diego, California, United States of America.
authors.forename: Anjan
authors.initials: A
authors.lastname: Debnath
authors.affiliation: Center for Discovery and Innovation in Parasitic Diseases, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Judy A
authors.initials: JA
authors.lastname: Sakanari
mesh_terms: D000328:Adult; D015766:Albendazole / Q000627:therapeutic use; D000818:Animals; D000871:Anthelmintics / Q000627:therapeutic use; D001310:Auranofin / Q000627:therapeutic use*; D017178:Brugia malayi / Q000187:drug effects; D002417:Cattle; D002460:Cell Line; D004049:Diethylcarbamazine / Q000627:therapeutic use; D058492:Drug Repositioning; D004605:Elephantiasis, Filarial / Q000188:drug therapy* / Q000469:parasitology; D005260:Female; D005369:Filaricides / Q000627:therapeutic use; D005849:Gerbillinae; D000882:Haplorhini; D006801:Humans; D007559:Ivermectin / Q000627:therapeutic use; D008117:Loa / Q000187:drug effects; D008118:Loiasis / Q000188:drug therapy* / Q000469:parasitology; D008842:Microfilariae / Q000187:drug effects*; D017181:Onchocerca volvulus / Q000187:drug effects; D009855:Onchocerciasis / Q000188:drug therapy* / Q000469:parasitology
chemical_list: D000871:Anthelmintics; D005369:Filaricides; D001310:Auranofin; D007559:Ivermectin; D015766:Albendazole; D004049:Diethylcarbamazine