Parasite neuropeptide biology: Seeding rational drug target selection?

Abstract

The rationale for identifying drug targets within helminth neuromuscular signalling systems is based on the premise that adequate nerve and muscle function is essential for many of the key behavioural determinants of helminth parasitism, including sensory perception/host location, invasion, locomotion/orientation, attachment, feeding and reproduction. This premise is validated by the tendency of current anthelmintics to act on classical neurotransmitter-gated ion channels present on helminth nerve and/or muscle, yielding therapeutic endpoints associated with paralysis and/or death. Supplementary to classical neurotransmitters, helminth nervous systems are peptide-rich and encompass associated biosynthetic and signal transduction components - putative drug targets that remain to be exploited by anthelmintic chemotherapy. At this time, no neuropeptide system-targeting lead compounds have been reported, and given that our basic knowledge of neuropeptide biology in parasitic helminths remains inadequate, the short-term prospects for such drugs remain poor. Here, we review current knowledge of neuropeptide signalling in Nematoda and Platyhelminthes, and highlight a suite of 19 protein families that yield deleterious phenotypes in helminth reverse genetics screens. We suggest that orthologues of some of these peptidergic signalling components represent appealing therapeutic targets in parasitic helminths.

Keywords: Anthelmintic; Nervous system; Neuromuscular; Receptor; Signalling.

Graphical abstract

Fig. 1

The amidated neuropeptide system of an adult female Schistosoma mansoni. Peptidyl α-hydroxylating monooxygenase (PHM)-immunoreactivity (IR) appears green (fluorescein isothiocyanate [FITC]-labelled secondary antibody) whilst filamentous actin in muscle fibres appears red (tetramethyl rhodamine isothiocyanate [TRITC]-labelled phalloidin). (A) Extensive PHM-IR in the paired cerebral ganglia (^∗), main nerve cords (MNC) and nerve processes innervating the oral sucker (Os), oesophagus (Oes), acetabulum (Ac), uterus (U) and gut (Gt) in the anterior region of a female schistosome. The outer surface of the fore body region is covered in immuno positive sensory endings (arrow heads). (B) PHM-IR just posterior to the oral sucker (Os) in one of the main nerve cords (MNC) and associated nerve net that provides branches to the numerous sensory endings (arrow heads) of the anterior-lateral forebody. Note that the tegument is not visible; body wall muscle (M). Scale bars: A = 30 μm; B = 12 μm.