Assessment of FDA-approved drugs against Strongyloides ratti in vitro and in vivo to identify potentially active drugs against strongyloidiasis

Abstract

Background Infections with Strongyloides stercoralis belong to the most neglected helminth diseases, and research and development (R&D) efforts on novel drugs are inadequate. Methods A commercially available library containing 1600 FDA-approved drugs was tested in vitro against Strongyloides ratti larvae (L3) at 100 µM. Hits (activity > 70%) were then evaluated against S. ratti adult worms at 10 µM. Morantel, prasterone, and levamisole were tested in the S. ratti rat model using dosages of 1–100 mg/kg. Results Seventy-one of the 1600 compounds tested against S. ratti L3 revealed activity above 70%. Of 64 compounds which progressed into the adult screen, seven compounds achieved death of all worms (benzethonium chloride, cetylpyridinium chloride, Gentian violet, methylbenzethonium chloride, morantel citrate, ivermectin, coumaphos), and another eight compounds had activity > 70%. Excluding topical and toxic compounds, three drugs progressed into in vivo studies. Prasterone lacked activity in vivo, while treatment with 100 mg/kg morantel and levamisole cured all rats. The highest in vivo activity was observed with levamisole, yielding a median effective dose (ED50) of 1.1 mg/kg. Conclusions Using a drug repurposing approach, our study identified levamisole as a potential backup drug for strongyloidiasis. Levamisole should be evaluated in exploratory clinical trials. Graphical Abstract

Comparative structure activity and target exploration of 1,2-diphenylethynes in Haemonchus contortus and Caenorhabditis elegans

“…Given the divergence in the nematocidal pharmacophore between H. contortus and C. elegans worms, the low-to-moderate activity against H. contortus adult worms, and the apparent lack of a conserved nematode drug target, the future development of UMW-9729 as a broad-spectrum anthelmintic may be challenging. Certainly, future work should focus on the development of a non-cytotoxic and non-mitotoxic compound (with adequate pharmacokinetic properties) which is active against parasitic stages of H. contortus and other socioeconomically important nematodes ( Keiser et al, 2016 ; Keiser and Häberli, 2021 ). Moreover, if a UMW-9729 analogue were established as a suitable front-runner candidate in vitro , it would be pivotal to also assess its antiparasitic activity in vivo .…”

Development and validation of an epithelial–mesenchymal transition-related gene signature for predicting prognosis

“…A study found that meticrane can target the PPAR signaling pathway and inhibit the reabsorption of sodium and chloride ions in distal convoluted tubules[ 39 ]. Morantel is the classic competitive antagonist of dihydro-β-erythroidine, which noncompetitively inhibits morantel-evoked currents[ 40 ]. Resveratrol has been reported to treat a variety of cancers, including papillary thyroid cancer and liver cancer[ 41 , 42 ].…”

Structure-activity relationship and target investigation of 2-aryl quinolines with nematocidal activity

“…2070; Swiss Tropical and Public Health Institute), (three weeks of age; male) Syrian golden hamsters (Janvier Laboratories, Le Genest-Saint-Isle, France) were orally infected with 140 L3s of A. ceylanicum or 150 L3s of N. americanus ; (three weeks of age; female) NMRI mice (Charles River Laboratories, Sulzfeld, Germany) were orally inoculated with 90 L3s of He. polygyrus ; (three weeks of age; female) C57BL/6NRj mice (Janvier Laboratories) were orally inoculated with 200 embryonated eggs of T. muris ; (three weeks of age; male) Wistar rats (Janvier Laboratories) were subcutaneously injected with 1300 L3s of S. ratti ( Keiser and Häberli, 2021 ). Faeces (containing eggs) collected from animals infected with A. ceylanicum , N. americanus , He.…”

“…To explore the anthelmintic activity of ABX464 on a parasitic species, here, we tested a series of analogues ( Shanley et al, 2024 ) on larvae of H. contortus to establish a structure-activity relationship (SAR). We further evaluated key derivatives of ABX464 on H. contortus adults and a panel of parasitic nematodes ( Keiser et al, 2016 ; Keiser and Häberli, 2021 ), and proceeded to infer the target(s) of ABX464 in H. contortus using TPP and in silico docking.…”