Repurposing auranofin as a lead candidate for treatment of lymphatic filariasis and onchocerciasis.
Identifieur interne : 001035 ( PubMed/Curation ); précédent : 001034; suivant : 001036Repurposing 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 [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 [ 1935-2735 ] ; 2015.
Descripteurs français
- KwdFr :
- Adulte, Albendazole (usage thérapeutique), Animaux, Antihelminthiques (usage thérapeutique), Auranofine (usage thérapeutique), Bovins, Brugia malayi (), Diéthylcarbamazine (usage thérapeutique), Femelle, Filaricides (usage thérapeutique), Filariose lymphatique (parasitologie), Filariose lymphatique (traitement médicamenteux), Gerbillinae, Haplorhini, Humains, Ivermectine (usage thérapeutique), Lignée cellulaire, Loa (), Loase (parasitologie), Loase (traitement médicamenteux), Microfilaria (), Onchocerca volvulus (), Onchocercose (parasitologie), Onchocercose (traitement médicamenteux), Repositionnement des médicaments.
- MESH :
- parasitologie : Filariose lymphatique, Loase, Onchocercose.
- traitement médicamenteux : Filariose lymphatique, Loase, Onchocercose.
- usage thérapeutique : Albendazole, Antihelminthiques, Auranofine, Diéthylcarbamazine, Filaricides, Ivermectine.
- Adulte, Animaux, Bovins, Brugia malayi, Femelle, Gerbillinae, Haplorhini, Humains, Lignée cellulaire, Loa, Microfilaria, Onchocerca volvulus, Repositionnement des médicaments.
English descriptors
- KwdEn :
- Adult, Albendazole (therapeutic use), Animals, Anthelmintics (therapeutic use), Auranofin (therapeutic use), Brugia malayi (drug effects), Cattle, Cell Line, Diethylcarbamazine (therapeutic use), Drug Repositioning, Elephantiasis, Filarial (drug therapy), Elephantiasis, Filarial (parasitology), Female, Filaricides (therapeutic use), Gerbillinae, Haplorhini, Humans, Ivermectin (therapeutic use), Loa (drug effects), Loiasis (drug therapy), Loiasis (parasitology), Microfilariae (drug effects), Onchocerca volvulus (drug effects), Onchocerciasis (drug therapy), Onchocerciasis (parasitology).
- MESH :
- chemical , therapeutic use : Albendazole, Anthelmintics, Auranofin, Diethylcarbamazine, Filaricides, Ivermectin.
- drug effects : Brugia malayi, Loa, Microfilariae, Onchocerca volvulus.
- drug therapy : Elephantiasis, Filarial, Loiasis, Onchocerciasis.
- parasitology : Elephantiasis, Filarial, Loiasis, Onchocerciasis.
- Adult, Animals, Cattle, Cell Line, Drug Repositioning, Female, Gerbillinae, Haplorhini, Humans.
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.
DOI: 10.1371/journal.pntd.0003534
PubMed: 25700363
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Mckerrow</name><affiliation wicri:level="1"><nlm:affiliation>Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, San Diego, California, United States of America.</nlm:affiliation><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></affiliation></author><author><name sortKey="Debnath, Anjan" sort="Debnath, Anjan" uniqKey="Debnath A" first="Anjan" last="Debnath">Anjan Debnath</name><affiliation wicri:level="1"><nlm:affiliation>Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, San Diego, California, United States of America.</nlm:affiliation><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></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="1"><nlm:affiliation>Center for Discovery and Innovation in Parasitic Diseases, University of California San Francisco, San Francisco, California, United States of America.</nlm:affiliation><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></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2015">2015</date><idno type="RBID">pubmed:25700363</idno><idno type="pmid">25700363</idno><idno type="doi">10.1371/journal.pntd.0003534</idno><idno type="wicri:Area/PubMed/Corpus">001035</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">001035</idno><idno type="wicri:Area/PubMed/Curation">001035</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Curation">001035</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">Repurposing auranofin as a lead candidate for treatment of lymphatic filariasis and onchocerciasis.</title><author><name sortKey="Bulman, Christina A" sort="Bulman, Christina A" uniqKey="Bulman C" first="Christina A" last="Bulman">Christina A. Bulman</name><affiliation wicri:level="1"><nlm:affiliation>Center for Discovery and Innovation in Parasitic Diseases, University of California San Francisco, San Francisco, California, United States of America.</nlm:affiliation><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></affiliation></author><author><name sortKey="Bidlow, Chelsea M" sort="Bidlow, Chelsea M" uniqKey="Bidlow C" first="Chelsea M" last="Bidlow">Chelsea M. Bidlow</name><affiliation wicri:level="1"><nlm:affiliation>Center for Discovery and Innovation in Parasitic Diseases, University of California San Francisco, San Francisco, California, United States of America.</nlm:affiliation><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></affiliation></author><author><name sortKey="Lustigman, Sara" sort="Lustigman, Sara" uniqKey="Lustigman S" first="Sara" last="Lustigman">Sara Lustigman</name><affiliation wicri:level="1"><nlm:affiliation>Lindsley F. Kimball Research Institute, New York Blood Center, New York, New York, United States of America.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Lindsley F. Kimball Research Institute, New York Blood Center, New York, New York</wicri:regionArea></affiliation></author><author><name sortKey="Cho Ngwa, Fidelis" sort="Cho Ngwa, Fidelis" uniqKey="Cho Ngwa F" first="Fidelis" last="Cho-Ngwa">Fidelis Cho-Ngwa</name><affiliation wicri:level="1"><nlm:affiliation>Department of Biochemistry and Molecular Biology, University of Buea, Buea, SW Region, Cameroon.</nlm:affiliation><country xml:lang="fr">Cameroun</country><wicri:regionArea>Department of Biochemistry and Molecular Biology, University of Buea, Buea, SW Region</wicri:regionArea></affiliation></author><author><name sortKey="Williams, David" sort="Williams, David" uniqKey="Williams D" first="David" last="Williams">David Williams</name><affiliation wicri:level="1"><nlm:affiliation>Department of Immunology and Microbiology, Rush University Medical Center, Chicago, Illinois, United States of America.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Immunology and Microbiology, Rush University Medical Center, Chicago, Illinois</wicri:regionArea></affiliation></author><author><name sortKey="Rasc N, Alberto A" sort="Rasc N, Alberto A" uniqKey="Rasc N A" first="Alberto A" last="Rasc N">Alberto A. Rasc N</name><affiliation wicri:level="1"><nlm: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.</nlm:affiliation><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, United States of America; Department of Chemistry, San Jose State University, San Jose, California</wicri:regionArea></affiliation></author><author><name sortKey="Tricoche, Nancy" sort="Tricoche, Nancy" uniqKey="Tricoche N" first="Nancy" last="Tricoche">Nancy Tricoche</name><affiliation wicri:level="1"><nlm:affiliation>Lindsley F. Kimball Research Institute, New York Blood Center, New York, New York, United States of America.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Lindsley F. Kimball Research Institute, New York Blood Center, New York, New York</wicri:regionArea></affiliation></author><author><name sortKey="Samje, Moses" sort="Samje, Moses" uniqKey="Samje M" first="Moses" last="Samje">Moses Samje</name><affiliation wicri:level="1"><nlm:affiliation>Department of Biochemistry and Molecular Biology, University of Buea, Buea, SW Region, Cameroon.</nlm:affiliation><country xml:lang="fr">Cameroun</country><wicri:regionArea>Department of Biochemistry and Molecular Biology, University of Buea, Buea, SW Region</wicri:regionArea></affiliation></author><author><name sortKey="Bell, Aaron" sort="Bell, Aaron" uniqKey="Bell A" first="Aaron" last="Bell">Aaron Bell</name><affiliation wicri:level="1"><nlm:affiliation>Lindsley F. Kimball Research Institute, New York Blood Center, New York, New York, United States of America.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Lindsley F. Kimball Research Institute, New York Blood Center, New York, New York</wicri:regionArea></affiliation></author><author><name sortKey="Suzuki, Brian" sort="Suzuki, Brian" uniqKey="Suzuki B" first="Brian" last="Suzuki">Brian Suzuki</name><affiliation wicri:level="1"><nlm:affiliation>Center for Discovery and Innovation in Parasitic Diseases, University of California San Francisco, San Francisco, California, United States of America.</nlm:affiliation><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></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="1"><nlm:affiliation>Center for Discovery and Innovation in Parasitic Diseases, University of California San Francisco, San Francisco, California, United States of America.</nlm:affiliation><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></affiliation></author><author><name sortKey="Supakorndej, Nonglak" sort="Supakorndej, Nonglak" uniqKey="Supakorndej N" first="Nonglak" last="Supakorndej">Nonglak Supakorndej</name><affiliation wicri:level="1"><nlm:affiliation>FilariaTech, Athens, Georgia, United States of America.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>FilariaTech, Athens, Georgia</wicri:regionArea></affiliation></author><author><name sortKey="Supakorndej, Prasit" sort="Supakorndej, Prasit" uniqKey="Supakorndej P" first="Prasit" last="Supakorndej">Prasit Supakorndej</name><affiliation wicri:level="1"><nlm:affiliation>Department of Infectious Diseases, University of Georgia, Athens, Georgia, United States of America.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Infectious Diseases, University of Georgia, Athens, Georgia</wicri:regionArea></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="1"><nlm:affiliation>Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, California, United States of America.</nlm:affiliation><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></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="1"><nlm:affiliation>UCSF Mass Spectrometry Facility, Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, California, United States of America.</nlm:affiliation><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></affiliation></author><author><name sortKey="Chen, Steven" sort="Chen, Steven" uniqKey="Chen S" first="Steven" last="Chen">Steven Chen</name><affiliation wicri:level="1"><nlm:affiliation>Small Molecule Discovery Center, University of California San Francisco, San Francisco, California, United States of America.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Small Molecule Discovery Center, University of California San Francisco, San Francisco, California</wicri:regionArea></affiliation></author><author><name sortKey="Wilson, Chris" sort="Wilson, Chris" uniqKey="Wilson C" first="Chris" last="Wilson">Chris Wilson</name><affiliation wicri:level="1"><nlm:affiliation>Small Molecule Discovery Center, University of California San Francisco, San Francisco, California, United States of America.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Small Molecule Discovery Center, University of California San Francisco, San Francisco, California</wicri:regionArea></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="1"><nlm:affiliation>Small Molecule Discovery Center, University of California San Francisco, San Francisco, California, United States of America.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Small Molecule Discovery Center, University of California San Francisco, San Francisco, California</wicri:regionArea></affiliation></author><author><name sortKey="Arkin, Michelle" sort="Arkin, Michelle" uniqKey="Arkin M" first="Michelle" last="Arkin">Michelle Arkin</name><affiliation wicri:level="1"><nlm:affiliation>Small Molecule Discovery Center, University of California San Francisco, San Francisco, California, United States of America.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Small Molecule Discovery Center, University of California San Francisco, San Francisco, California</wicri:regionArea></affiliation></author><author><name sortKey="Gut, Jiri" sort="Gut, Jiri" uniqKey="Gut J" first="Jiri" last="Gut">Jiri Gut</name><affiliation wicri:level="1"><nlm:affiliation>Center for Discovery and Innovation in Parasitic Diseases, University of California San Francisco, San Francisco, California, United States of America.</nlm:affiliation><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></affiliation></author><author><name sortKey="Franklin, Chris" sort="Franklin, Chris" uniqKey="Franklin C" first="Chris" last="Franklin">Chris Franklin</name><affiliation wicri:level="1"><nlm:affiliation>Center for Discovery and Innovation in Parasitic Diseases, University of California San Francisco, San Francisco, California, United States of America.</nlm:affiliation><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></affiliation></author><author><name sortKey="Marcellino, Chris" sort="Marcellino, Chris" uniqKey="Marcellino C" first="Chris" last="Marcellino">Chris Marcellino</name><affiliation wicri:level="1"><nlm:affiliation>Case Western Reserve University School of Medicine, Cleveland, Ohio, United States of America.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Case Western Reserve University School of Medicine, Cleveland, Ohio</wicri:regionArea></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="1"><nlm:affiliation>Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, San Diego, California, United States of America.</nlm:affiliation><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></affiliation></author><author><name sortKey="Debnath, Anjan" sort="Debnath, Anjan" uniqKey="Debnath A" first="Anjan" last="Debnath">Anjan Debnath</name><affiliation wicri:level="1"><nlm:affiliation>Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, San Diego, California, United States of America.</nlm:affiliation><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></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="1"><nlm:affiliation>Center for Discovery and Innovation in Parasitic Diseases, University of California San Francisco, San Francisco, California, United States of America.</nlm:affiliation><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></affiliation></author></analytic><series><title level="j">PLoS neglected tropical diseases</title><idno type="eISSN">1935-2735</idno><imprint><date when="2015" type="published">2015</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Adult</term><term>Albendazole (therapeutic use)</term><term>Animals</term><term>Anthelmintics (therapeutic use)</term><term>Auranofin (therapeutic use)</term><term>Brugia malayi (drug effects)</term><term>Cattle</term><term>Cell Line</term><term>Diethylcarbamazine (therapeutic use)</term><term>Drug Repositioning</term><term>Elephantiasis, Filarial (drug therapy)</term><term>Elephantiasis, Filarial (parasitology)</term><term>Female</term><term>Filaricides (therapeutic use)</term><term>Gerbillinae</term><term>Haplorhini</term><term>Humans</term><term>Ivermectin (therapeutic use)</term><term>Loa (drug effects)</term><term>Loiasis (drug therapy)</term><term>Loiasis (parasitology)</term><term>Microfilariae (drug effects)</term><term>Onchocerca volvulus (drug effects)</term><term>Onchocerciasis (drug therapy)</term><term>Onchocerciasis (parasitology)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Adulte</term><term>Albendazole (usage thérapeutique)</term><term>Animaux</term><term>Antihelminthiques (usage thérapeutique)</term><term>Auranofine (usage thérapeutique)</term><term>Bovins</term><term>Brugia malayi ()</term><term>Diéthylcarbamazine (usage thérapeutique)</term><term>Femelle</term><term>Filaricides (usage thérapeutique)</term><term>Filariose lymphatique (parasitologie)</term><term>Filariose lymphatique (traitement médicamenteux)</term><term>Gerbillinae</term><term>Haplorhini</term><term>Humains</term><term>Ivermectine (usage thérapeutique)</term><term>Lignée cellulaire</term><term>Loa ()</term><term>Loase (parasitologie)</term><term>Loase (traitement médicamenteux)</term><term>Microfilaria ()</term><term>Onchocerca volvulus ()</term><term>Onchocercose (parasitologie)</term><term>Onchocercose (traitement médicamenteux)</term><term>Repositionnement des médicaments</term></keywords><keywords scheme="MESH" type="chemical" qualifier="therapeutic use" xml:lang="en"><term>Albendazole</term><term>Anthelmintics</term><term>Auranofin</term><term>Diethylcarbamazine</term><term>Filaricides</term><term>Ivermectin</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Brugia malayi</term><term>Loa</term><term>Microfilariae</term><term>Onchocerca volvulus</term></keywords><keywords scheme="MESH" qualifier="drug therapy" xml:lang="en"><term>Elephantiasis, Filarial</term><term>Loiasis</term><term>Onchocerciasis</term></keywords><keywords scheme="MESH" qualifier="parasitologie" xml:lang="fr"><term>Filariose lymphatique</term><term>Loase</term><term>Onchocercose</term></keywords><keywords scheme="MESH" qualifier="parasitology" xml:lang="en"><term>Elephantiasis, Filarial</term><term>Loiasis</term><term>Onchocerciasis</term></keywords><keywords scheme="MESH" qualifier="traitement médicamenteux" xml:lang="fr"><term>Filariose lymphatique</term><term>Loase</term><term>Onchocercose</term></keywords><keywords scheme="MESH" qualifier="usage thérapeutique" xml:lang="fr"><term>Albendazole</term><term>Antihelminthiques</term><term>Auranofine</term><term>Diéthylcarbamazine</term><term>Filaricides</term><term>Ivermectine</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Adult</term><term>Animals</term><term>Cattle</term><term>Cell Line</term><term>Drug Repositioning</term><term>Female</term><term>Gerbillinae</term><term>Haplorhini</term><term>Humans</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Adulte</term><term>Animaux</term><term>Bovins</term><term>Brugia malayi</term><term>Femelle</term><term>Gerbillinae</term><term>Haplorhini</term><term>Humains</term><term>Lignée cellulaire</term><term>Loa</term><term>Microfilaria</term><term>Onchocerca volvulus</term><term>Repositionnement des médicaments</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">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.</div></front></TEI><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">25700363</PMID><DateCreated><Year>2015</Year><Month>02</Month><Day>21</Day></DateCreated><DateCompleted><Year>2016</Year><Month>01</Month><Day>22</Day></DateCompleted><DateRevised><Year>2017</Year><Month>02</Month><Day>20</Day></DateRevised><Article PubModel="Electronic-eCollection"><Journal><ISSN IssnType="Electronic">1935-2735</ISSN><JournalIssue CitedMedium="Internet"><Volume>9</Volume><Issue>2</Issue><PubDate><Year>2015</Year><Month>Feb</Month></PubDate></JournalIssue><Title>PLoS neglected tropical diseases</Title><ISOAbbreviation>PLoS Negl Trop Dis</ISOAbbreviation></Journal><ArticleTitle>Repurposing auranofin as a lead candidate for treatment of lymphatic filariasis and onchocerciasis.</ArticleTitle><Pagination><MedlinePgn>e0003534</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.1371/journal.pntd.0003534</ELocationID><Abstract><AbstractText>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.</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Bulman</LastName><ForeName>Christina A</ForeName><Initials>CA</Initials><AffiliationInfo><Affiliation>Center for Discovery and Innovation in Parasitic Diseases, University of California San Francisco, San Francisco, California, United States of America.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Bidlow</LastName><ForeName>Chelsea M</ForeName><Initials>CM</Initials><AffiliationInfo><Affiliation>Center for Discovery and Innovation in Parasitic Diseases, University of California San Francisco, San Francisco, California, United States of America.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Lustigman</LastName><ForeName>Sara</ForeName><Initials>S</Initials><AffiliationInfo><Affiliation>Lindsley F. Kimball Research Institute, New York Blood Center, New York, New York, United States of America.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Cho-Ngwa</LastName><ForeName>Fidelis</ForeName><Initials>F</Initials><AffiliationInfo><Affiliation>Department of Biochemistry and Molecular Biology, University of Buea, Buea, SW Region, Cameroon.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Williams</LastName><ForeName>David</ForeName><Initials>D</Initials><AffiliationInfo><Affiliation>Department of Immunology and Microbiology, Rush University Medical Center, Chicago, Illinois, United States of America.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Rascón</LastName><ForeName>Alberto A</ForeName><Initials>AA</Initials><Suffix>Jr</Suffix><AffiliationInfo><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.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Tricoche</LastName><ForeName>Nancy</ForeName><Initials>N</Initials><AffiliationInfo><Affiliation>Lindsley F. Kimball Research Institute, New York Blood Center, New York, New York, United States of America.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Samje</LastName><ForeName>Moses</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Department of Biochemistry and Molecular Biology, University of Buea, Buea, SW Region, Cameroon.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Bell</LastName><ForeName>Aaron</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Lindsley F. Kimball Research Institute, New York Blood Center, New York, New York, United States of America.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Suzuki</LastName><ForeName>Brian</ForeName><Initials>B</Initials><AffiliationInfo><Affiliation>Center for Discovery and Innovation in Parasitic Diseases, University of California San Francisco, San Francisco, California, United States of America.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Lim</LastName><ForeName>K C</ForeName><Initials>KC</Initials><AffiliationInfo><Affiliation>Center for Discovery and Innovation in Parasitic Diseases, University of California San Francisco, San Francisco, California, United States of America.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Supakorndej</LastName><ForeName>Nonglak</ForeName><Initials>N</Initials><AffiliationInfo><Affiliation>FilariaTech, Athens, Georgia, United States of America.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Supakorndej</LastName><ForeName>Prasit</ForeName><Initials>P</Initials><AffiliationInfo><Affiliation>Department of Infectious Diseases, University of Georgia, Athens, Georgia, United States of America.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Wolfe</LastName><ForeName>Alan R</ForeName><Initials>AR</Initials><AffiliationInfo><Affiliation>Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, California, United States of America.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Knudsen</LastName><ForeName>Giselle M</ForeName><Initials>GM</Initials><AffiliationInfo><Affiliation>UCSF Mass Spectrometry Facility, Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, California, United States of America.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Chen</LastName><ForeName>Steven</ForeName><Initials>S</Initials><AffiliationInfo><Affiliation>Small Molecule Discovery Center, University of California San Francisco, San Francisco, California, United States of America.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Wilson</LastName><ForeName>Chris</ForeName><Initials>C</Initials><AffiliationInfo><Affiliation>Small Molecule Discovery Center, University of California San Francisco, San Francisco, California, United States of America.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Ang</LastName><ForeName>Kean-Hooi</ForeName><Initials>KH</Initials><AffiliationInfo><Affiliation>Small Molecule Discovery Center, University of California San Francisco, San Francisco, California, United States of America.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Arkin</LastName><ForeName>Michelle</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Small Molecule Discovery Center, University of California San Francisco, San Francisco, California, United States of America.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Gut</LastName><ForeName>Jiri</ForeName><Initials>J</Initials><AffiliationInfo><Affiliation>Center for Discovery and Innovation in Parasitic Diseases, University of California San Francisco, San Francisco, California, United States of America.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Franklin</LastName><ForeName>Chris</ForeName><Initials>C</Initials><AffiliationInfo><Affiliation>Center for Discovery and Innovation in Parasitic Diseases, University of California San Francisco, San Francisco, California, United States of America.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Marcellino</LastName><ForeName>Chris</ForeName><Initials>C</Initials><AffiliationInfo><Affiliation>Case Western Reserve University School of Medicine, Cleveland, Ohio, United States of America.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>McKerrow</LastName><ForeName>James H</ForeName><Initials>JH</Initials><AffiliationInfo><Affiliation>Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, San Diego, California, United States of America.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Debnath</LastName><ForeName>Anjan</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, San Diego, California, United States of America.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Sakanari</LastName><ForeName>Judy A</ForeName><Initials>JA</Initials><AffiliationInfo><Affiliation>Center for Discovery and Innovation in Parasitic Diseases, University of California San Francisco, San Francisco, California, United States of America.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><GrantList CompleteYN="Y"><Grant><GrantID>GM103481</GrantID><Acronym>GM</Acronym><Agency>NIGMS NIH HHS</Agency><Country>United States</Country></Grant></GrantList><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType><PublicationType UI="D052061">Research Support, N.I.H., Extramural</PublicationType><PublicationType UI="D013485">Research Support, Non-U.S. Gov't</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2015</Year><Month>02</Month><Day>20</Day></ArticleDate></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>PLoS Negl Trop Dis</MedlineTA><NlmUniqueID>101291488</NlmUniqueID><ISSNLinking>1935-2727</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D000871">Anthelmintics</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D005369">Filaricides</NameOfSubstance></Chemical><Chemical><RegistryNumber>3H04W2810V</RegistryNumber><NameOfSubstance UI="D001310">Auranofin</NameOfSubstance></Chemical><Chemical><RegistryNumber>70288-86-7</RegistryNumber><NameOfSubstance UI="D007559">Ivermectin</NameOfSubstance></Chemical><Chemical><RegistryNumber>F4216019LN</RegistryNumber><NameOfSubstance UI="D015766">Albendazole</NameOfSubstance></Chemical><Chemical><RegistryNumber>V867Q8X3ZD</RegistryNumber><NameOfSubstance UI="D004049">Diethylcarbamazine</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><CommentsCorrectionsList><CommentsCorrections RefType="Cites"><RefSource>Parasitol Today. 1992 May;8(5):168-71</RefSource><PMID Version="1">15463607</PMID></CommentsCorrections><CommentsCorrections RefType="Cites"><RefSource>J Biol Chem. 2008 Jun 27;283(26):17898-907</RefSource><PMID 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