Evaluation of an FDA approved library against laboratory models of human intestinal nematode infections. Issue 1 (December 2016)

• Record Type: Journal Article
• Authors: Keiser, Jennifer; Panic, Gordana; Adelfio, Roberto; Cowan, Noemi; Vargas, Mireille; Scandale, Ivan
• Is Part Of: Parasites & vectors. Volume 9:Issue 1(2016)
• Page Start: 1
• Page End: 10
• Publication Date: 2016-12
• Subjects: FDA library -- Soil-transmitted helminthiasis -- Drug sensitivity assay -- Trichuris muris -- Ancylostoma ceylanicum -- Heligmosomoides polygyrus; Parasitism -- Periodicals; Parasites -- Periodicals; Vector-pathogen relationships -- Periodicals; Animals as carriers of disease -- Periodicals; Insects as carriers of disease -- Periodicals; 616.96
• DOI: 10.1186/s13071-016-1616-0
• Languages: English
• ISSNs: 1756-3305

Abstract

Abstract Background Treatment options for infections with soil-transmitted helminths (STH) -Ascaris lumbricoides, Trichuris trichiura and the two hookworm species, Ancylostoma duodenale andNecator americanus - are limited despite their considerable global health burden. The aim of the present study was to test the activity of an openly available FDA library against laboratory models of human intestinal nematode infections. Methods All 1, 600 drugs were first screened againstAncylostoma ceylanicum third-stage larvae (L3). Active compounds were scrutinized and toxic compounds, drugs indicated solely for topical use, and already well-studied anthelmintics were excluded. The remaining hit compounds were tested in parallel againstTrichuris muris first-stage larvae (L1), Heligmosomoides polygyrus third-stage larvae (L3), and adult stages of the three species in vitro. In vivo studies were performed in theH. polygyrus andT. muris mice models. Results Fifty-four of the 1, 600 compounds tested revealed an activity of > 60 % againstA. ceylanicum L3 (hit rate of 3.4 %), following incubation at 200 μM for 72 h. Twelve compounds progressed into further screens. AdultA. ceylanicum were the least affected (1/12 compounds active at 50 μM), while eight of the 12 test compounds revealed activity againstT. muris L1 (100 μM) and adults (50 μM), andH. polygyrus L3 (200 μM). Trichlorfon was the only compound active against all stages ofA. ceylanicum, H. polygyrus andT. muris . In addition, trichlorfon achieved high worm burden reductions of 80.1 and 98.9 %, following a single oral dose of 200 mg/kg in theT. muris andH. polygyrus mouse model, respectively. Conclusion Drug screening on the larval stages of intestinal parasitic nematodes is feasible using small libraries and important given the empty drug discovery and development pipeline for STH infections. Differences and commonalities in drug activities across the different STH species and stages were confirmed. Hits identified might serve as a starting point for drug discovery for STH.