Repurposing auranofin as a lead candidate for treatment of lymphatic filariasis and onchocerciasis.
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 t...
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Public Library of Science (PLoS)
2015-02-01
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| Series: | PLoS Neglected Tropical Diseases |
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| author | Christina A Bulman Chelsea M Bidlow Sara Lustigman Fidelis Cho-Ngwa David Williams Alberto A Rascón Nancy Tricoche Moses Samje Aaron Bell Brian Suzuki K C Lim Nonglak Supakorndej Prasit Supakorndej Alan R Wolfe Giselle M Knudsen Steven Chen Chris Wilson Kean-Hooi Ang Michelle Arkin Jiri Gut Chris Franklin Chris Marcellino James H McKerrow Anjan Debnath Judy A Sakanari |
| author_facet | Christina A Bulman Chelsea M Bidlow Sara Lustigman Fidelis Cho-Ngwa David Williams Alberto A Rascón Nancy Tricoche Moses Samje Aaron Bell Brian Suzuki K C Lim Nonglak Supakorndej Prasit Supakorndej Alan R Wolfe Giselle M Knudsen Steven Chen Chris Wilson Kean-Hooi Ang Michelle Arkin Jiri Gut Chris Franklin Chris Marcellino James H McKerrow Anjan Debnath Judy A Sakanari |
| author_sort | Christina A Bulman |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-1872fa3e64e84c4c88486f9960a5d481 |
| institution | OA Journals |
| issn | 1935-2727 1935-2735 |
| language | English |
| publishDate | 2015-02-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Neglected Tropical Diseases |
| spelling | doaj-art-1872fa3e64e84c4c88486f9960a5d4812025-08-20T02:15:15ZengPublic Library of Science (PLoS)PLoS Neglected Tropical Diseases1935-27271935-27352015-02-0192e000353410.1371/journal.pntd.0003534Repurposing auranofin as a lead candidate for treatment of lymphatic filariasis and onchocerciasis.Christina A BulmanChelsea M BidlowSara LustigmanFidelis Cho-NgwaDavid WilliamsAlberto A RascónNancy TricocheMoses SamjeAaron BellBrian SuzukiK C LimNonglak SupakorndejPrasit SupakorndejAlan R WolfeGiselle M KnudsenSteven ChenChris WilsonKean-Hooi AngMichelle ArkinJiri GutChris FranklinChris MarcellinoJames H McKerrowAnjan DebnathJudy A SakanariTwo 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.https://journals.plos.org/plosntds/article/file?id=10.1371/journal.pntd.0003534&type=printable |
| spellingShingle | Christina A Bulman Chelsea M Bidlow Sara Lustigman Fidelis Cho-Ngwa David Williams Alberto A Rascón Nancy Tricoche Moses Samje Aaron Bell Brian Suzuki K C Lim Nonglak Supakorndej Prasit Supakorndej Alan R Wolfe Giselle M Knudsen Steven Chen Chris Wilson Kean-Hooi Ang Michelle Arkin Jiri Gut Chris Franklin Chris Marcellino James H McKerrow Anjan Debnath Judy A Sakanari Repurposing auranofin as a lead candidate for treatment of lymphatic filariasis and onchocerciasis. PLoS Neglected Tropical Diseases |
| title | Repurposing auranofin as a lead candidate for treatment of lymphatic filariasis and onchocerciasis. |
| title_full | Repurposing auranofin as a lead candidate for treatment of lymphatic filariasis and onchocerciasis. |
| title_fullStr | Repurposing auranofin as a lead candidate for treatment of lymphatic filariasis and onchocerciasis. |
| title_full_unstemmed | Repurposing auranofin as a lead candidate for treatment of lymphatic filariasis and onchocerciasis. |
| title_short | Repurposing auranofin as a lead candidate for treatment of lymphatic filariasis and onchocerciasis. |
| title_sort | repurposing auranofin as a lead candidate for treatment of lymphatic filariasis and onchocerciasis |
| url | https://journals.plos.org/plosntds/article/file?id=10.1371/journal.pntd.0003534&type=printable |
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