Serine/threonine phosphatases in socioeconomically important parasitic nematodes—Prospects as novel drug targets?

Abstract

Little is known about the fundamental biology of parasitic nematodes (=roundworms) that cause serious diseases, affecting literally billions of animals and humans worldwide. Unlocking the biology of these neglected pathogens using modern technologies will yield crucial and profound knowledge of their molecular biology, and could lead to new treatment and control strategies. Supported by studies in the free-living nematode, Caenorhabditis elegans, some recent investigations have provided improved insights into selected protein phosphatases (PPs) of economically important parasitic nematodes (Strongylida). In the present article, we review this progress and assess the potential of serine/threonine phosphatase (STP) genes and/or their products as targets for new nematocidal drugs. Current information indicates that some small molecules, known to specifically inhibit PPs, might be developed as nematocides. For instance, some cantharidin analogues are known to display exquisite PP-inhibitor activity, which indicates that some of them could be designed and tailored to specifically inhibit selected STPs of nematodes. This information provides prospects for the discovery of an entirely novel class of nematocides, which is of paramount importance, given the serious problems linked to anthelmintic resistance in parasitic nematode populations of livestock, and has the potential to lead to significant biotechnological outcomes.

Proteomic identification of Galectin-11 and 14 ligands from Haemonchus contortus

“…A significant number of proteins (n = 19) with enzyme activity in adults were identified, and similar proteins have been described in other 'omic studies, suggesting that many of these enzymes of the protease family are conserved and evolutionarily related in nematodes (Campbell et al 2011;Ghedin et al 2007;Schwarz et al 2013). A notable protease identified in the adult stage, is zinc metallopeptidase (M13 protease or neprilysin).…”

Ascaris suum draft genome

“…Interestingly, the high nucleotide variability linked to the key elements of translation machinery did not relate to a bias in synonymous SNPs, suggesting that many mutations accumulate in particular 'hotspots' and/or are tolerated, but do not compromise either the structure or the function of this machinery. The least variable genes encoded various (druggable) 16,17 serine/threonine phosphatases (n 5 17) as well as numerous receptors, channels and transporters, for which there was an unusually strong bias towards synonymous SNPs, reinforcing their potential as intervention targets.…”

“…Given their key roles, many of these enzymes are proposed as targets for anti-parasitic compounds and/or vaccines [16][17][18] . Equally, the range of receptor and channel proteins identified here are interesting because many common anthelmintics bind such targets 19 .…”

Panel docking of small-molecule libraries — Prospects to improve efficiency of lead compound discovery

“…The methodology described here might provide a means of improving the efficiency and cost-effectiveness of target and lead identification. Since the concept of panel docking is reliant on a high degree of similarity in the structural fold of the target, the method should also be applicable to other target classes, such as serine/threonine phosphatases which have recently emerged as novel targets in the fight against parasitism (Campbell et al, 2011).…”