Repurposing Auranofin as a Lead Candidate for Treatment of Lymphatic Filariasis and Onchocerciasis

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.

Phase I Clinical Trial Results of Auranofin, a Novel Antiparasitic Agent

“…We and others (6,(8)(9)(10)(11)(12)(13)(14) have shown that auranofin holds promise for treating both protozoal and helminthic diseases. When the use of auranofin in therapy was approved by the FDA in 1985, safety and pharmacokinetics/pharmacodynamics (PK/PD) data requirements were much less stringent.…”

“…Oral auranofin was also effective in rodent models of amebic colitis and liver abscess (6) and in in vitro and in vivo models with metronidazole-sensitive and -resistant strains of Giardia intestinalis (7). In addition, auranofin has the potential to be a broad-spectrum antiparasitic agent, as in vitro and/or in vivo efficacy has been demonstrated for trichomoniasis (Kirk Land, University of the Pacific, personal communication), Cryptosporidium infections (8), filariasis (9), Toxoplasma gondii infections (10), Trypanosoma brucei infections (11), Leishmania infantum infections (12), and schistosomiasis (13,14).…”

Synthesis, Molecular Structure and Anti-Onchocercal Studies of 1-(Phthalazin-1(2H)-one)[(Pyridin-2-yl)ethylidene]hydrazone

“…A single x-ray analysis performed on APN (Figure 4) confirmed the proposed structure of the hydralazine Schiff base showing clearly the exocyclic C=N double bond (bond length 1.308 A˚) of the hydralazine moiety [1] [21] and the N-H bond of bond length 0.918 A˚ [19] 3.5. Activity of Compounds on Microfilariae/Macrofilariae and Cytotoxicity APN was screened on the juvenile form of the O. ochengi beginning at the highest compound concentration of 20 µg/mL.…”

“…The FDA-approved compound, auranofin which has been reported to be active on adult worms at 10 µM, was used as positive control for the adult worm assays [19]. Ivermectin (Mectizan®) was used as the positive control drug for the microfilariae assays.…”

Isolation and characterization of filaricidal compounds from the stem bark of Voacanga africana, a plant used in the traditional treatment of onchocerciasis in Cameroon

“…12 μl of 5mM stock test compound mixed with 988 μl of CCM was then added into each of quadruplicate wells to give a single final concentration of 30 μM. Four nodular masses each, were used in the negative control (2% dimethyl sulfoxide in CCM only) and in the positive control (10 µM auranofin, a gold conjugated compound) (Bulman et al, 2015) wells in which each well also received only one nodular mass. After 5 days incubation, adult male viability was assessed based on motility scores using an inverted microscope.…”