Discovery of Anthelmintic Drug Targets and Drugs Using Chokepoints in Nematode Metabolic Pathways

Abstract

Parasitic roundworm infections plague more than 2 billion people (1/3 of humanity) and cause drastic losses in crops and livestock. New anthelmintic drugs are urgently needed as new drug resistance and environmental concerns arise. A “chokepoint reaction” is defined as a reaction that either consumes a unique substrate or produces a unique product. A chokepoint analysis provides a systematic method of identifying novel potential drug targets. Chokepoint enzymes were identified in the genomes of 10 nematode species, and the intersection and union of all chokepoint enzymes were found. By studying and experimentally testing available compounds known to target proteins orthologous to nematode chokepoint proteins in public databases, this study uncovers features of chokepoints that make them successful drug targets. Chemogenomic screening was performed on drug-like compounds from public drug databases to find existing compounds that target homologs of nematode chokepoints. The compounds were prioritized based on chemical properties frequently found in successful drugs and were experimentally tested using Caenorhabditis elegans. Several drugs that are already known anthelmintic drugs and novel candidate targets were identified. Seven of the compounds were tested in Caenorhabditis elegans and three yielded a detrimental phenotype. One of these three drug-like compounds, Perhexiline, also yielded a deleterious effect in Haemonchus contortus and Onchocerca lienalis, two nematodes with divergent forms of parasitism. Perhexiline, known to affect the fatty acid oxidation pathway in mammals, caused a reduction in oxygen consumption rates in C. elegans and genome-wide gene expression profiles provided an additional confirmation of its mode of action. Computational modeling of Perhexiline and its target provided structural insights regarding its binding mode and specificity. Our lists of prioritized drug targets and drug-like compounds have potential to expedite the discovery of new anthelmintic drugs with broad-spectrum efficacy.

Plant-Based Solutions to Global Livestock Anthelmintic Resistance

“…When feasible, using the latter method will provide more accurate, reproducible results. Benzimidazoles synthe c chemical α-and β-tubulin monomers (Demeler et al 2013) Dasa nib synthe c chemical protein kinases (Taylor et al 2013)…”

“…synthe c chemical eggs (Taylor et al 2013) Flavopiridol synthe c chemical protein kinases (Taylor et al 2013) Invermec n synthe c chemical eggs (Taylor et al 2013) Monacrosporium salinum secondary metabolites larvicidal (Liu et al 2015) Monacrosporium thaumasium secondary metabolites larvicidal (Vilela et al 2013) Bacillus thuringiensis Cry14A growth and development (Wei et al 2003) Perspec ves using a variety of solvents (e.g., ethanol, acetone, chloroform, methanol, water). Each solvent will cause plant cells to release different categories of metabolites based on polarity and hydrophilicity.…”

Haemonchus Contortus and Ovine Host: A Retrospective Review.

“…Thanks to modern technology, there have been nearly 300 species of parasitic helminths known to be human parasite. Additionally, livestock, crops and pets are all victims of parasitic helminths, which cause extreme effects on the human population as well [3].…”

Predatory activity of Butlerius nematodes and nematophagous fungi against Haemonchus contortus infective larvae

“…Massive infections of this parasite cause the death of animals, especially young ones, which are more susceptible (GILLEARD, 2013). This and other parasites are normally controlled with chemical anthelmintic drugs (TAYLOR et al, 2013). This method helps to reduce the parasitic burden in the animals, but it has some disadvantages, including the imminent emergence of anthelmintic resistance in the parasites (MÁRQUEZ-LARA, 2003;FORTES et al, 2013).…”