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

Moses Samje,Nancy Tricoche,Alan R. Wolfe,Brian M. Suzuki ,Fidelis Cho-Ngwa,K. C. Lim,Jiří Gut ,P. Supakorndej ,Anjan Debnath,Chelsea M. Bidlow,Aaron Bell,David L. Williams ,Steven Chen,James H. McKerrow,Chris Wilson,Christina Bulman ,N. Supakorndej ,Giselle M. Knudsen,Chris Franklin,Chris Marcellino,Kean-Hooi Ang,Alberto A. Rascón ,Michelle R. Arkin ,Sara Lustigman,Judy Sakanari

doi:10.1371/journal.pntd.0003534

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.

Highlights

River blindness and lymphatic filariasis (LF) are two major neglected diseases caused by filariid nematodes that, together, affect an estimated 145 million people worldwide in mostly poor, developing countries [1,2]
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 Onchocerca volvulus and lymphatic filariasis is caused by Brugia malayi, B. timori, and Wuchereria bancrofti

Summary

Introduction

River blindness and lymphatic filariasis (LF) are two major neglected diseases caused by filariid nematodes that, together, affect an estimated 145 million people worldwide in mostly poor, developing countries [1,2]. River blindness, caused by the filariid nematode Onchocerca volvulus, is a chronic, debilitating disease and a major cause of infectious blindness. The adult worms, or macrofilariae, reside in subcutaneous tissues where females release the early larval stage, microfilariae, into the skin. Adult worms can reproduce for up to 10–14 years, releasing millions of microfilariae over an infected individual’s lifetime [3]. The adult worms reside in the lymphatic tissues where females release microfilariae into the circulation. The microfilariae are ingested by mosquitoes and develop into the infectious larval stage. With LF, the chronic condition is characterized by pain and severe lymphedema often involving the arms, legs, breasts and genitalia, as well as elephantiasis, all of which may lead to social stigma and economic loss to those afflicted [4,5]

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