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PLoS Negl Trop Dis. 2015 Feb 20;9(2):e0003534. doi: 10.1371/journal.pntd.0003534. eCollection 2015 Feb.

Repurposing auranofin as a lead candidate for treatment of lymphatic filariasis and onchocerciasis.

Author information

1
Center for Discovery and Innovation in Parasitic Diseases, University of California San Francisco, San Francisco, California, United States of America.
2
Lindsley F. Kimball Research Institute, New York Blood Center, New York, New York, United States of America.
3
Department of Biochemistry and Molecular Biology, University of Buea, Buea, SW Region, Cameroon.
4
Department of Immunology and Microbiology, Rush University Medical Center, Chicago, Illinois, United States of America.
5
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.
6
FilariaTech, Athens, Georgia, United States of America.
7
Department of Infectious Diseases, University of Georgia, Athens, Georgia, United States of America.
8
Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, California, United States of America.
9
UCSF Mass Spectrometry Facility, Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, California, United States of America.
10
Small Molecule Discovery Center, University of California San Francisco, San Francisco, California, United States of America.
11
Case Western Reserve University School of Medicine, Cleveland, Ohio, United States of America.
12
Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, San Diego, California, United States of America.

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.

PMID:
25700363
PMCID:
PMC4336141
DOI:
10.1371/journal.pntd.0003534
[Indexed for MEDLINE]
Free PMC Article

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