Journal Article

Evaluation of an FDA approved library against laboratory models of human intestinal nematode infections

Cowan, Noemi, Vargas, Mireille, Keiser, Jennifer, Adelfio, Roberto, Scandale, Ivan, Panic, Gordana

2016

Overview

Background Treatment options for infections with soil-transmitted helminths (STH) - Ascaris lumbricoides , Trichuris trichiura and the two hookworm species, Ancylostoma duodenale and Necator 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 against Ancylostoma 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 against Trichuris 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 the H. polygyrus and T. muris mice models. Results Fifty-four of the 1,600 compounds tested revealed an activity of > 60 % against A. ceylanicum L3 (hit rate of 3.4 %), following incubation at 200 μM for 72 h. Twelve compounds progressed into further screens. Adult A. ceylanicum were the least affected (1/12 compounds active at 50 μM), while eight of the 12 test compounds revealed activity against T. muris L1 (100 μM) and adults (50 μM), and H. polygyrus L3 (200 μM). Trichlorfon was the only compound active against all stages of A. ceylanicum , H. polygyrus and T. 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 the T. muris and H. 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.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V
• Subject: active ingredients / Adult / adults / Ancylostoma - drug effects / Ancylostoma ceylanicum / animal models / Animals / Anthelmintics - pharmacology / Anthelmintics - therapeutic use / Ascaris lumbricoides / Ascaris lumbricoides - drug effects / Biomedical and Life Sciences / Biomedicine / Cricetinae / Disease Models, Animal / Drug Evaluation, Preclinical / drugs / Entomology / Evaluation / Female / Heligmosomoides polygyrus / hookworms / Humans / in vivo studies / Infectious Diseases / Intestinal Diseases, Parasitic - drug therapy / larvae / Male / Mesocricetus / Mice / Mice, Inbred C57BL / Necator americanus / Necator americanus - drug effects / Nematoda - drug effects / nematode infections / Nematode Infections - drug therapy / Parasitology / Practice guidelines (Medicine) / Roundworm infections / screening / Small Molecule Libraries - pharmacology / Small Molecule Libraries - standards / Small Molecule Libraries - therapeutic use / toxic substances / trichlorfon / Trichuris - drug effects / Trichuris muris / Trichuris trichiura / Tropical Medicine / United States / United States Food and Drug Administration / Veterinary Medicine/Veterinary Science / Virology