Structural characterisation and pharmacology of KHEYLRFamide (AF2) and KSAYMRFamide (PF3/AF8) from Haemonchus contortus

The FMRFamide-related peptides (FaRPs), KHEYLRFamide (AF2) and KSAYMRFamide (PF3) were structurally characterised from the parasitic nematode of sheep, Haemonchus contortus (MH isolate). Both peptides were sequenced in a single gas-phase sequencing run and their structure confirmed by mass spectrometry which identified peptides of 920 Da (C-terminally amidated AF2) and 902/918 Da (C-terminally amidated non-oxidised/oxidised PF3, respectively). AF2 had inhibitory effects on H. contortus muscle and inhibited acetylcholine (ACh, 10 mu M)-induced contractions, with a threshold for activity of I mu M. PF3 induced concentration-dependent contractions of H. contortus (activity threshold, 10 nM) and enhanced ACh contractions. Compared with the MH isolate, an isolate of H. contortus which has reduced sensitivity to cholinergic drugs (Lawes isolate) was less sensitive to the effects of PF3. The concentration-response curves for the cholinergic compounds ACh and levamisole (LEV), and PF3, but not a control, KPNFIRFamide (PF4), showed a statistically similar shift. This study implicates PF3 in the modulation of cholinergic function in H. contortus. (C) 1999 Elsevier Science B.V. All rights reserved.

FMRFamide-related peptides (FaRPs) in helminth parasites

Neuropeptides are ubiquitous intercellular signalling molecules in all Metazoa with nervous systems. Research over the past 10 years has confirmed through immunocytochemistry that neuropeptides are widespread and abundant in the nervous systems of helminth parasites. Biochemical isolation and characterisation studies have indentified the primary structures of numerous structurally-related peptides in helminths, the best studied being the FMRFamide-related peptides (FaRPs). While to date only four FaRPs have been identified from platyhelminths, some 60 FaRPs or FaRP-like peptides have been isolated or predicted for nematodes. Preliminary physiological studies have shown that FaRPs are strongly myoactive, but with quire different actions in the two groups of helminth parasite. The absence of FaRPs from vertebrates suggests compounds with a high affinity for FaRP receptors are likely to have selective effects against helminths and, if protected from degradation, could have therapeutic potential.