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

Abstract

BackgroundTreatment 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.MethodsAll 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.ResultsFifty-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.ConclusionDrug 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13071-016-1616-0) contains supplementary material, which is available to authorized users.

Sertraline, Paroxetine, and Chlorpromazine Are Rapidly Acting Anthelmintic Drugs Capable of Clinical Repurposing

“…Chlorpromazine gained widespread use in the 1950’s as the first neuroleptic drug, and is thought to primarily act through antagonism of DA D2 receptors 21 . Chlorpromazine has been reported to decrease embryonic survival in C. elegans and Haemonchus contortus (a parasitic nematode of ruminants) 22 , kill L3 larvae of Ancylostoma ceylanicum (hookworm) 23 , and reduce the motility of Dirofilaria immitis (canine heartworm) 24 . Exogenously applied DA can also reduce movements of Meloidogyne incognita and Heterodera glycines , two parasitic nematodes of plants 11 .…”

Computationally-guided drug repurposing enables the discovery of kinase targets and inhibitors as new schistosomicidal agents

“…Imatinib has already been identified as a possible drug-repurposing candidate based on the homology between the human gene target and a gene in the Schistosoma genome during its annotation [ 35 – 37 ]. The second line treatments have recently been identified from larval and follow-up adult phenotypic screening [ 38 ]. These independent observations validate the approach used here.…”

Unpacking the Pathogen Box—An Open Source Tool for Fighting Neglected Tropical Disease

“…Current front‐line strategies for morbidity control involve large‐scale periodic use of anthelmintic drugs, including mebendazole (MMV003152, 645 ) . The Pathogen Box features two compounds in this category, the antihistamine clemastine (MMV637229, 646 ) and the antispasmodic zoxzolamine (MMV003270, 647 ), both of which showed moderate anthelmintic activity …”