Repurposing Auranofin as a Lead Candidate for Treatment of Lymphatic Filariasis and Onchocerciasis
Identifieur interne : 000F04 ( Pmc/Checkpoint ); précédent : 000F03; suivant : 000F05Repurposing Auranofin as a Lead Candidate for Treatment of Lymphatic Filariasis and Onchocerciasis
Auteurs : Christina A. Bulman [États-Unis] ; Chelsea M. Bidlow [États-Unis] ; Sara Lustigman [États-Unis] ; Fidelis Cho-Ngwa [Cameroun] ; David Williams [États-Unis] ; Alberto A. Rasc N Jr [États-Unis] ; Nancy Tricoche [États-Unis] ; Moses Samje [Cameroun] ; Aaron Bell [États-Unis] ; Brian Suzuki [États-Unis] ; K. C. Lim [États-Unis] ; Nonglak Supakorndej [États-Unis] ; Prasit Supakorndej [États-Unis] ; Alan R. Wolfe [États-Unis] ; Giselle M. Knudsen [États-Unis] ; Steven Chen [États-Unis] ; Chris Wilson [États-Unis] ; Kean-Hooi Ang [États-Unis] ; Michelle Arkin [États-Unis] ; Jiri Gut [États-Unis] ; Chris Franklin [États-Unis] ; Chris Marcellino [États-Unis] ; James H. Mckerrow [États-Unis] ; Anjan Debnath [États-Unis] ; Judy A. Sakanari [États-Unis]Source :
- PLoS Neglected Tropical Diseases [ 1935-2727 ] ; 2015.
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
Url:
DOI: 10.1371/journal.pntd.0003534
PubMed: 25700363
PubMed Central: 4336141
Affiliations:
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PMC:4336141Le document en format XML
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Repurposing Auranofin as a Lead Candidate for Treatment of Lymphatic Filariasis and Onchocerciasis</title>
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<author><name sortKey="Suzuki, Brian" sort="Suzuki, Brian" uniqKey="Suzuki B" first="Brian" last="Suzuki">Brian Suzuki</name>
<affiliation wicri:level="2"><nlm:aff id="aff001"><addr-line>Center for Discovery and Innovation in Parasitic Diseases, University of California San Francisco, San Francisco, California, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Center for Discovery and Innovation in Parasitic Diseases, University of California San Francisco, San Francisco, California</wicri:regionArea>
<placeName><region type="state">Californie</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Lim, K C" sort="Lim, K C" uniqKey="Lim K" first="K. C." last="Lim">K. C. Lim</name>
<affiliation wicri:level="2"><nlm:aff id="aff001"><addr-line>Center for Discovery and Innovation in Parasitic Diseases, University of California San Francisco, San Francisco, California, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Center for Discovery and Innovation in Parasitic Diseases, University of California San Francisco, San Francisco, California</wicri:regionArea>
<placeName><region type="state">Californie</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Supakorndej, Nonglak" sort="Supakorndej, Nonglak" uniqKey="Supakorndej N" first="Nonglak" last="Supakorndej">Nonglak Supakorndej</name>
<affiliation wicri:level="2"><nlm:aff id="aff006"><addr-line>FilariaTech, Athens, Georgia, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>FilariaTech, Athens, Georgia</wicri:regionArea>
<placeName><region type="state">Géorgie (États-Unis)</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Supakorndej, Prasit" sort="Supakorndej, Prasit" uniqKey="Supakorndej P" first="Prasit" last="Supakorndej">Prasit Supakorndej</name>
<affiliation wicri:level="2"><nlm:aff id="aff007"><addr-line>Department of Infectious Diseases, University of Georgia, Athens, Georgia, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Infectious Diseases, University of Georgia, Athens, Georgia</wicri:regionArea>
<placeName><region type="state">Géorgie (États-Unis)</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Wolfe, Alan R" sort="Wolfe, Alan R" uniqKey="Wolfe A" first="Alan R." last="Wolfe">Alan R. Wolfe</name>
<affiliation wicri:level="2"><nlm:aff id="aff008"><addr-line>Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, California, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, California</wicri:regionArea>
<placeName><region type="state">Californie</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Knudsen, Giselle M" sort="Knudsen, Giselle M" uniqKey="Knudsen G" first="Giselle M." last="Knudsen">Giselle M. Knudsen</name>
<affiliation wicri:level="2"><nlm:aff id="aff009"><addr-line>UCSF Mass Spectrometry Facility, Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, California, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>UCSF Mass Spectrometry Facility, Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, California</wicri:regionArea>
<placeName><region type="state">Californie</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Chen, Steven" sort="Chen, Steven" uniqKey="Chen S" first="Steven" last="Chen">Steven Chen</name>
<affiliation wicri:level="2"><nlm:aff id="aff010"><addr-line>Small Molecule Discovery Center, University of California San Francisco, San Francisco, California, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Small Molecule Discovery Center, University of California San Francisco, San Francisco, California</wicri:regionArea>
<placeName><region type="state">Californie</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Wilson, Chris" sort="Wilson, Chris" uniqKey="Wilson C" first="Chris" last="Wilson">Chris Wilson</name>
<affiliation wicri:level="2"><nlm:aff id="aff010"><addr-line>Small Molecule Discovery Center, University of California San Francisco, San Francisco, California, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Small Molecule Discovery Center, University of California San Francisco, San Francisco, California</wicri:regionArea>
<placeName><region type="state">Californie</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Ang, Kean Hooi" sort="Ang, Kean Hooi" uniqKey="Ang K" first="Kean-Hooi" last="Ang">Kean-Hooi Ang</name>
<affiliation wicri:level="2"><nlm:aff id="aff010"><addr-line>Small Molecule Discovery Center, University of California San Francisco, San Francisco, California, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Small Molecule Discovery Center, University of California San Francisco, San Francisco, California</wicri:regionArea>
<placeName><region type="state">Californie</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Arkin, Michelle" sort="Arkin, Michelle" uniqKey="Arkin M" first="Michelle" last="Arkin">Michelle Arkin</name>
<affiliation wicri:level="2"><nlm:aff id="aff010"><addr-line>Small Molecule Discovery Center, University of California San Francisco, San Francisco, California, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Small Molecule Discovery Center, University of California San Francisco, San Francisco, California</wicri:regionArea>
<placeName><region type="state">Californie</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Gut, Jiri" sort="Gut, Jiri" uniqKey="Gut J" first="Jiri" last="Gut">Jiri Gut</name>
<affiliation wicri:level="2"><nlm:aff id="aff001"><addr-line>Center for Discovery and Innovation in Parasitic Diseases, University of California San Francisco, San Francisco, California, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Center for Discovery and Innovation in Parasitic Diseases, University of California San Francisco, San Francisco, California</wicri:regionArea>
<placeName><region type="state">Californie</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Franklin, Chris" sort="Franklin, Chris" uniqKey="Franklin C" first="Chris" last="Franklin">Chris Franklin</name>
<affiliation wicri:level="2"><nlm:aff id="aff001"><addr-line>Center for Discovery and Innovation in Parasitic Diseases, University of California San Francisco, San Francisco, California, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Center for Discovery and Innovation in Parasitic Diseases, University of California San Francisco, San Francisco, California</wicri:regionArea>
<placeName><region type="state">Californie</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Marcellino, Chris" sort="Marcellino, Chris" uniqKey="Marcellino C" first="Chris" last="Marcellino">Chris Marcellino</name>
<affiliation wicri:level="2"><nlm:aff id="aff011"><addr-line>Case Western Reserve University School of Medicine, Cleveland, Ohio, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Case Western Reserve University School of Medicine, Cleveland, Ohio</wicri:regionArea>
<placeName><region type="state">Ohio</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Mckerrow, James H" sort="Mckerrow, James H" uniqKey="Mckerrow J" first="James H." last="Mckerrow">James H. Mckerrow</name>
<affiliation wicri:level="2"><nlm:aff id="aff012"><addr-line>Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, San Diego, California, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, San Diego, California</wicri:regionArea>
<placeName><region type="state">Californie</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Debnath, Anjan" sort="Debnath, Anjan" uniqKey="Debnath A" first="Anjan" last="Debnath">Anjan Debnath</name>
<affiliation wicri:level="2"><nlm:aff id="aff012"><addr-line>Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, San Diego, California, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, San Diego, California</wicri:regionArea>
<placeName><region type="state">Californie</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Sakanari, Judy A" sort="Sakanari, Judy A" uniqKey="Sakanari J" first="Judy A." last="Sakanari">Judy A. Sakanari</name>
<affiliation wicri:level="2"><nlm:aff id="aff001"><addr-line>Center for Discovery and Innovation in Parasitic Diseases, University of California San Francisco, San Francisco, California, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Center for Discovery and Innovation in Parasitic Diseases, University of California San Francisco, San Francisco, California</wicri:regionArea>
<placeName><region type="state">Californie</region>
</placeName>
</affiliation>
</author>
</analytic>
<series><title level="j">PLoS Neglected Tropical Diseases</title>
<idno type="ISSN">1935-2727</idno>
<idno type="eISSN">1935-2735</idno>
<imprint><date when="2015">2015</date>
</imprint>
</series>
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</sourceDesc>
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<profileDesc><textClass></textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en"><p>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 <italic>Onchocerca volvulus</italic>
and <italic>Brugia malayi</italic>
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 <italic>Brugia</italic>
spp. and <italic>Onchocerca ochengi</italic>
, third-stage larvae (L3s) of <italic>Onchocerca volvulus</italic>
, and the microfilariae of both <italic>O. ochengi</italic>
and <italic>Loa loa</italic>
. We found that auranofin, a gold-containing drug used for rheumatoid arthritis, was effective <italic>in vitro</italic>
in killing both <italic>Brugia</italic>
spp. and <italic>O. ochengi</italic>
adult worms and in inhibiting the molting of L3s of <italic>O. volvulus</italic>
with IC<sub>50</sub>
values in the low micromolar to nanomolar range. Auranofin had an approximately 43-fold higher IC<sub>50</sub>
against the microfilariae of <italic>L. loa</italic>
compared with the IC<sub>50</sub>
for adult female <italic>O. ochengi</italic>
, which may be beneficial if used in areas where <italic>Onchocerca</italic>
and <italic>Brugia</italic>
are co-endemic with <italic>L. loa</italic>
, to prevent severe adverse reactions to the drug-induced death of <italic>L. loa</italic>
microfilariae. Further testing indicated that auranofin is also effective in reducing <italic>Brugia</italic>
adult worm burden in infected gerbils and that auranofin may be targeting the thioredoxin reductase in this nematode.</p>
</div>
</front>
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<pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">PLoS Negl Trop Dis</journal-id>
<journal-id journal-id-type="iso-abbrev">PLoS Negl Trop Dis</journal-id>
<journal-id journal-id-type="publisher-id">plos</journal-id>
<journal-id journal-id-type="pmc">plosntds</journal-id>
<journal-title-group><journal-title>PLoS Neglected Tropical Diseases</journal-title>
</journal-title-group>
<issn pub-type="ppub">1935-2727</issn>
<issn pub-type="epub">1935-2735</issn>
<publisher><publisher-name>Public Library of Science</publisher-name>
<publisher-loc>San Francisco, CA USA</publisher-loc>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">25700363</article-id>
<article-id pub-id-type="pmc">4336141</article-id>
<article-id pub-id-type="doi">10.1371/journal.pntd.0003534</article-id>
<article-id pub-id-type="publisher-id">PNTD-D-14-01497</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject>
</subj-group>
</article-categories>
<title-group><article-title>Repurposing Auranofin as a Lead Candidate for Treatment of Lymphatic Filariasis and Onchocerciasis</article-title>
<alt-title alt-title-type="running-head">Auranofin for Treatment of LF & Onchocerciasis</alt-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Bulman</surname>
<given-names>Christina A.</given-names>
</name>
<xref ref-type="aff" rid="aff001"><sup>1</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Bidlow</surname>
<given-names>Chelsea M.</given-names>
</name>
<xref ref-type="aff" rid="aff001"><sup>1</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Lustigman</surname>
<given-names>Sara</given-names>
</name>
<xref ref-type="aff" rid="aff002"><sup>2</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Cho-Ngwa</surname>
<given-names>Fidelis</given-names>
</name>
<xref ref-type="aff" rid="aff003"><sup>3</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Williams</surname>
<given-names>David</given-names>
</name>
<xref ref-type="aff" rid="aff004"><sup>4</sup>
</xref>
</contrib>
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<given-names>Alberto A.</given-names>
</name>
<xref ref-type="aff" rid="aff001"><sup>1</sup>
</xref>
<xref ref-type="aff" rid="aff005"><sup>5</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Tricoche</surname>
<given-names>Nancy</given-names>
</name>
<xref ref-type="aff" rid="aff002"><sup>2</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Samje</surname>
<given-names>Moses</given-names>
</name>
<xref ref-type="aff" rid="aff003"><sup>3</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Bell</surname>
<given-names>Aaron</given-names>
</name>
<xref ref-type="aff" rid="aff002"><sup>2</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Suzuki</surname>
<given-names>Brian</given-names>
</name>
<xref ref-type="aff" rid="aff001"><sup>1</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Lim</surname>
<given-names>K. C.</given-names>
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<xref ref-type="aff" rid="aff001"><sup>1</sup>
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<contrib contrib-type="author"><name><surname>Supakorndej</surname>
<given-names>Nonglak</given-names>
</name>
<xref ref-type="aff" rid="aff006"><sup>6</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Supakorndej</surname>
<given-names>Prasit</given-names>
</name>
<xref ref-type="aff" rid="aff007"><sup>7</sup>
</xref>
</contrib>
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<given-names>Alan R.</given-names>
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<xref ref-type="aff" rid="aff008"><sup>8</sup>
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<given-names>Giselle M.</given-names>
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<xref ref-type="aff" rid="aff009"><sup>9</sup>
</xref>
</contrib>
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<given-names>Steven</given-names>
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<xref ref-type="aff" rid="aff010"><sup>10</sup>
</xref>
</contrib>
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<given-names>Chris</given-names>
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<xref ref-type="aff" rid="aff010"><sup>10</sup>
</xref>
</contrib>
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<given-names>Kean-Hooi</given-names>
</name>
<xref ref-type="aff" rid="aff010"><sup>10</sup>
</xref>
</contrib>
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<given-names>Michelle</given-names>
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<xref ref-type="aff" rid="aff010"><sup>10</sup>
</xref>
</contrib>
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<given-names>Jiri</given-names>
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<xref ref-type="aff" rid="aff001"><sup>1</sup>
</xref>
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<given-names>Chris</given-names>
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<xref ref-type="aff" rid="aff001"><sup>1</sup>
</xref>
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<contrib contrib-type="author"><name><surname>Marcellino</surname>
<given-names>Chris</given-names>
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<xref ref-type="aff" rid="aff011"><sup>11</sup>
</xref>
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<given-names>James H.</given-names>
</name>
<xref ref-type="aff" rid="aff012"><sup>12</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Debnath</surname>
<given-names>Anjan</given-names>
</name>
<xref ref-type="aff" rid="aff012"><sup>12</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Sakanari</surname>
<given-names>Judy A.</given-names>
</name>
<xref ref-type="aff" rid="aff001"><sup>1</sup>
</xref>
<xref rid="cor001" ref-type="corresp">*</xref>
</contrib>
</contrib-group>
<aff id="aff001"><label>1</label>
<addr-line>Center for Discovery and Innovation in Parasitic Diseases, University of California San Francisco, San Francisco, California, United States of America</addr-line>
</aff>
<aff id="aff002"><label>2</label>
<addr-line>Lindsley F. Kimball Research Institute, New York Blood Center, New York, New York, United States of America</addr-line>
</aff>
<aff id="aff003"><label>3</label>
<addr-line>Department of Biochemistry and Molecular Biology, University of Buea, Buea, SW Region, Cameroon</addr-line>
</aff>
<aff id="aff004"><label>4</label>
<addr-line>Department of Immunology and Microbiology, Rush University Medical Center, Chicago, Illinois, United States of America</addr-line>
</aff>
<aff id="aff005"><label>5</label>
<addr-line>Department of Chemistry, San Jose State University, San Jose, California, United States of America</addr-line>
</aff>
<aff id="aff006"><label>6</label>
<addr-line>FilariaTech, Athens, Georgia, United States of America</addr-line>
</aff>
<aff id="aff007"><label>7</label>
<addr-line>Department of Infectious Diseases, University of Georgia, Athens, Georgia, United States of America</addr-line>
</aff>
<aff id="aff008"><label>8</label>
<addr-line>Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, California, United States of America</addr-line>
</aff>
<aff id="aff009"><label>9</label>
<addr-line>UCSF Mass Spectrometry Facility, Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, California, United States of America</addr-line>
</aff>
<aff id="aff010"><label>10</label>
<addr-line>Small Molecule Discovery Center, University of California San Francisco, San Francisco, California, United States of America</addr-line>
</aff>
<aff id="aff011"><label>11</label>
<addr-line>Case Western Reserve University School of Medicine, Cleveland, Ohio, United States of America</addr-line>
</aff>
<aff id="aff012"><label>12</label>
<addr-line>Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, San Diego, California, United States of America</addr-line>
</aff>
<contrib-group><contrib contrib-type="editor"><name><surname>Gasser</surname>
<given-names>Robin B.</given-names>
</name>
<role>Editor</role>
<xref ref-type="aff" rid="edit1"></xref>
</contrib>
</contrib-group>
<aff id="edit1"><addr-line>University of Melbourne, AUSTRALIA</addr-line>
</aff>
<author-notes><fn fn-type="conflict" id="coi001"><p>I have read the journal’s policy and the authors of this manuscript have the following competing interests: NS is the owner of and currently runs FilariaTech, a commercial company. Additionally, two authors, NS and PS, are married. SL is a deputy editor of PLoS NTD. This does not alter our adherence to all PLOS NTDs policies on sharing data and materials.</p>
</fn>
<fn fn-type="con" id="contrib001"><p>Conceived and designed the experiments: CAB CMB SL FCN DW AAR AD JAS. Performed the experiments: CAB CMB SL FCN DW AAR NT MS AB BS KCL NS PS ARW GMK SC KHA CF JAS. Analyzed the data: CAB CMB SL FCN DW AAR NT MS AB ARW GMK SC CW KHA CF CM JHM AD JAS. Contributed reagents/materials/analysis tools: NS PS ARW GMK SC CW KHA MA JG CM. Wrote the paper: CAB CMB SL FCN DW AAR AB MS AB NS PS ARW CW KHA CF CM JHM AD JAS.</p>
</fn>
<corresp id="cor001">* E-mail: <email>Judy.Sakanari@ucsf.edu</email>
</corresp>
</author-notes>
<pub-date pub-type="epub"><day>20</day>
<month>2</month>
<year>2015</year>
</pub-date>
<pub-date pub-type="collection"><month>2</month>
<year>2015</year>
</pub-date>
<volume>9</volume>
<issue>2</issue>
<elocation-id>e0003534</elocation-id>
<history><date date-type="received"><day>29</day>
<month>8</month>
<year>2014</year>
</date>
<date date-type="accepted"><day>12</day>
<month>1</month>
<year>2015</year>
</date>
</history>
<permissions><copyright-year>2015</copyright-year>
<copyright-holder>Bulman et al</copyright-holder>
<license xlink:href="http://creativecommons.org/licenses/by/4.0/"><license-p>This is an open access article distributed under the terms of the <ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">Creative Commons Attribution License</ext-link>
, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited</license-p>
</license>
</permissions>
<self-uri content-type="pdf" xlink:type="simple" xlink:href="pntd.0003534.pdf"></self-uri>
<abstract><p>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 <italic>Onchocerca volvulus</italic>
and <italic>Brugia malayi</italic>
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 <italic>Brugia</italic>
spp. and <italic>Onchocerca ochengi</italic>
, third-stage larvae (L3s) of <italic>Onchocerca volvulus</italic>
, and the microfilariae of both <italic>O. ochengi</italic>
and <italic>Loa loa</italic>
. We found that auranofin, a gold-containing drug used for rheumatoid arthritis, was effective <italic>in vitro</italic>
in killing both <italic>Brugia</italic>
spp. and <italic>O. ochengi</italic>
adult worms and in inhibiting the molting of L3s of <italic>O. volvulus</italic>
with IC<sub>50</sub>
values in the low micromolar to nanomolar range. Auranofin had an approximately 43-fold higher IC<sub>50</sub>
against the microfilariae of <italic>L. loa</italic>
compared with the IC<sub>50</sub>
for adult female <italic>O. ochengi</italic>
, which may be beneficial if used in areas where <italic>Onchocerca</italic>
and <italic>Brugia</italic>
are co-endemic with <italic>L. loa</italic>
, to prevent severe adverse reactions to the drug-induced death of <italic>L. loa</italic>
microfilariae. Further testing indicated that auranofin is also effective in reducing <italic>Brugia</italic>
adult worm burden in infected gerbils and that auranofin may be targeting the thioredoxin reductase in this nematode.</p>
</abstract>
<abstract abstract-type="summary"><title>Author Summary</title>
<p>Onchocerciasis or river blindness, and lymphatic filariasis, which can lead to disfiguring elephantiasis, are two neglected tropical diseases that affect millions of people, primarily in developing countries. Both diseases are caused by filariid nematodes; onchocerciasis is caused by <italic>Onchocerca volvulus</italic>
and lymphatic filariasis is caused by <italic>Brugia malayi</italic>
, <italic>B. timori</italic>
, and <italic>Wuchereria bancrofti</italic>
. Currently, there are no drugs available that are highly efficacious against adult worms; existing drugs mainly kill the first-stage larvae (microfilariae). While these drugs can reduce the transmission of infections in a population, the adult filariids (macrofilariae) can continue to produce microfilariae and perpetuate the cycle of infection. Finding a drug that could kill the adult worms would be an important tool in eliminating onchocerciasis and lymphatic filariasis. To identify potential macrofilaricidal drugs, we developed a high throughput screening method to test FDA-approved drugs on adult <italic>Brugia</italic>
spp., which serves as a model for <italic>O. volvulus</italic>
. Using this screening method, we identified a drug called auranofin that kills adult <italic>Onchocerca</italic>
and adult <italic>Brugia</italic>
spp. <italic>in vitro</italic>
, inhibits the molting of <italic>O. volvulus</italic>
L3s, and reduces the worm burden in an <italic>in vivo</italic>
gerbil-<italic>B. pahangi</italic>
model system. Auranofin is known to inhibit a critical enzyme called thioredoxin reductase in some parasite species, and subsequent testing of the effects of auranofin on the thioredoxin reductase of <italic>Brugia</italic>
indicates that this may be auranofin’s mode of action in this nematode as well.</p>
</abstract>
<funding-group><funding-statement>This work was funded by the Bill & Melinda Gates Foundation (<ext-link ext-link-type="uri" xlink:href="http://www.gatesfoundation.org/">http://www.gatesfoundation.org/</ext-link>
) grant # OPP1017584. JHM & JAS. Mass spectrometry was performed in the UCSF MS Facility (<ext-link ext-link-type="uri" xlink:href="https://msf.ucsf.edu/">https://msf.ucsf.edu/</ext-link>
), funded by GM103481. GMK. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.</funding-statement>
</funding-group>
<counts><fig-count count="4"></fig-count>
<table-count count="2"></table-count>
<page-count count="18"></page-count>
</counts>
<custom-meta-group><custom-meta id="data-availability"><meta-name>Data Availability</meta-name>
<meta-value>All relevant data are within the paper and its Supporting Information files.</meta-value>
</custom-meta>
</custom-meta-group>
</article-meta>
<notes><title>Data Availability</title>
<p>All relevant data are within the paper and its Supporting Information files.</p>
</notes>
</front>
</pmc>
<affiliations><list><country><li>Cameroun</li>
<li>États-Unis</li>
</country>
<region><li>Californie</li>
<li>Géorgie (États-Unis)</li>
<li>Illinois</li>
<li>Ohio</li>
<li>État de New York</li>
</region>
</list>
<tree><country name="États-Unis"><region name="Californie"><name sortKey="Bulman, Christina A" sort="Bulman, Christina A" uniqKey="Bulman C" first="Christina A." last="Bulman">Christina A. Bulman</name>
</region>
<name sortKey="Ang, Kean Hooi" sort="Ang, Kean Hooi" uniqKey="Ang K" first="Kean-Hooi" last="Ang">Kean-Hooi Ang</name>
<name sortKey="Arkin, Michelle" sort="Arkin, Michelle" uniqKey="Arkin M" first="Michelle" last="Arkin">Michelle Arkin</name>
<name sortKey="Bell, Aaron" sort="Bell, Aaron" uniqKey="Bell A" first="Aaron" last="Bell">Aaron Bell</name>
<name sortKey="Bidlow, Chelsea M" sort="Bidlow, Chelsea M" uniqKey="Bidlow C" first="Chelsea M." last="Bidlow">Chelsea M. Bidlow</name>
<name sortKey="Chen, Steven" sort="Chen, Steven" uniqKey="Chen S" first="Steven" last="Chen">Steven Chen</name>
<name sortKey="Debnath, Anjan" sort="Debnath, Anjan" uniqKey="Debnath A" first="Anjan" last="Debnath">Anjan Debnath</name>
<name sortKey="Franklin, Chris" sort="Franklin, Chris" uniqKey="Franklin C" first="Chris" last="Franklin">Chris Franklin</name>
<name sortKey="Gut, Jiri" sort="Gut, Jiri" uniqKey="Gut J" first="Jiri" last="Gut">Jiri Gut</name>
<name sortKey="Knudsen, Giselle M" sort="Knudsen, Giselle M" uniqKey="Knudsen G" first="Giselle M." last="Knudsen">Giselle M. Knudsen</name>
<name sortKey="Lim, K C" sort="Lim, K C" uniqKey="Lim K" first="K. C." last="Lim">K. C. Lim</name>
<name sortKey="Lustigman, Sara" sort="Lustigman, Sara" uniqKey="Lustigman S" first="Sara" last="Lustigman">Sara Lustigman</name>
<name sortKey="Marcellino, Chris" sort="Marcellino, Chris" uniqKey="Marcellino C" first="Chris" last="Marcellino">Chris Marcellino</name>
<name sortKey="Mckerrow, James H" sort="Mckerrow, James H" uniqKey="Mckerrow J" first="James H." last="Mckerrow">James H. Mckerrow</name>
<name sortKey="Rasc N Jr, Alberto A" sort="Rasc N Jr, Alberto A" uniqKey="Rasc N Jr A" first="Alberto A." last="Rasc N Jr">Alberto A. Rasc N Jr</name>
<name sortKey="Rasc N Jr, Alberto A" sort="Rasc N Jr, Alberto A" uniqKey="Rasc N Jr A" first="Alberto A." last="Rasc N Jr">Alberto A. Rasc N Jr</name>
<name sortKey="Sakanari, Judy A" sort="Sakanari, Judy A" uniqKey="Sakanari J" first="Judy A." last="Sakanari">Judy A. Sakanari</name>
<name sortKey="Supakorndej, Nonglak" sort="Supakorndej, Nonglak" uniqKey="Supakorndej N" first="Nonglak" last="Supakorndej">Nonglak Supakorndej</name>
<name sortKey="Supakorndej, Prasit" sort="Supakorndej, Prasit" uniqKey="Supakorndej P" first="Prasit" last="Supakorndej">Prasit Supakorndej</name>
<name sortKey="Suzuki, Brian" sort="Suzuki, Brian" uniqKey="Suzuki B" first="Brian" last="Suzuki">Brian Suzuki</name>
<name sortKey="Tricoche, Nancy" sort="Tricoche, Nancy" uniqKey="Tricoche N" first="Nancy" last="Tricoche">Nancy Tricoche</name>
<name sortKey="Williams, David" sort="Williams, David" uniqKey="Williams D" first="David" last="Williams">David Williams</name>
<name sortKey="Wilson, Chris" sort="Wilson, Chris" uniqKey="Wilson C" first="Chris" last="Wilson">Chris Wilson</name>
<name sortKey="Wolfe, Alan R" sort="Wolfe, Alan R" uniqKey="Wolfe A" first="Alan R." last="Wolfe">Alan R. Wolfe</name>
</country>
<country name="Cameroun"><noRegion><name sortKey="Cho Ngwa, Fidelis" sort="Cho Ngwa, Fidelis" uniqKey="Cho Ngwa F" first="Fidelis" last="Cho-Ngwa">Fidelis Cho-Ngwa</name>
</noRegion>
<name sortKey="Samje, Moses" sort="Samje, Moses" uniqKey="Samje M" first="Moses" last="Samje">Moses Samje</name>
</country>
</tree>
</affiliations>
</record>
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