Philanthotoxin-433 (PhTX-433) is an active component of the venom from the Egyptian digger wasp, Philanthus triangulum. PhTX-433 inhibits several excitatory ligand-gated ion channels, and to improve selectivity two synthetic analogues, PhTX-343 and PhTX-12, were developed. Previous work showed a 22-fold selectivity of PhTX-12 over PhTX-343 for embryonic muscle-type nicotinic acetylcholine receptors (nAChRs) in TE671 cells. We investigated their inhibition of different neuronal nAChR subunit combinations as well as of embryonic muscle receptors expressed in Xenopus oocytes. Whole-cell currents in response to application of acetylcholine alone or co-applied with PhTX analogue were studied by using two-electrode voltage-clamp. α3β4 nAChRs were most sensitive to PhTX-343 (IC50 = 12 nM at −80 mV) with α4β4, α4β2, α3β2, α7 and α1β1γδ being 5, 26, 114, 422 and 992 times less sensitive. In contrast α1β1γδ was most sensitive to PhTX-12 along with α3β4 (IC50 values of 100 nM) with α4β4, α4β2, α3β2 and α7 being 3, 3, 26 and 49 times less sensitive. PhTX-343 inhibition was strongly voltage-dependent for all subunit combinations except α7, whereas this was not the case for PhTX-12 for which weak voltage dependence was observed. We conclude that PhTX-343 mainly acts as an open-channel blocker of nAChRs with strong subtype selectivity.

Insect toxins comprise a diverse array of chemicals ranging from small molecules, polyamines and peptide toxins. Many target nervous system and neuromuscular ion channels and so rapidly affect the behaviour of animals to which the toxin is applied or injected. Other modes of action have also been identified. Wasps, bees, flies, beetles and ants generate a rich arsenal of channel-active toxins, some of which offer selective pharmacological probes that target particular ion channels, while others act on more than one type of channel. Philanthotoxins from the digger wasp have been fruitful in adding to our understanding of ligand-gated ion channels in the nervous system and at neuromuscular junctions. Fire ants produce the toxic alkaloid solenopsin, a molecule which has stimulated attempts to generate synthetic compounds with insecticidal activity. Apamin from bee venom targets calcium-activated potassium channels which can in turn control the release of neuropeptides. Melittin, another bee venom component, is a membrane-acting peptide. The saliva of the assassin bug contains toxins that target the voltage-gated calcium channels of their insect prey. Certain beetles produce diamphotoxin, a haemolytic peptide toxin with traditional use as an arrow poison and others generate leptinotarsin with similar properties. Mastoparan is a powerful peptide toxin from wasp venom. Its toxic actions can be engineered out leaving a potent antimicrobial molecule of interest. Here we describe the modes of action of such compounds and evaluate their potential as neuroactive pharmacological tools and candidate lead molecules for insect control and as therapeutic candidates with potential antimicrobial, antiviral and anti-cancer applications.

is an active component of the venom from the Egyptian digger wasp, Philanthus triangulum. PhTX-433 non-selectively inhibits several excitatory ligandgated ion channels, and we recently showed that its synthetic analogue, PhTX-343, exhibits strong selectivity for neuronal over muscle-type nicotinic acetylcholine receptors (nAChRs).Here we examined the action of seventeen analogues of PhTX-343 against ganglionic (α3β4) and brain (α4β2) nAChRs expressed in Xenopus oocytes by using two-electrode voltage-clamp at 100 mV. IC50 values for PhTX-343 inhibition of α3β4 and α4β2 receptors were 7.7 nM and 80 nM, respectively. All of the studied analogues had significantly higher potency at α3β4 nAChRs with IC50 values as low as 0.16 nM and with up to a 91-fold selectivity for α3β4 over α4β2 receptors. We conclude that PhTX-343 analogues displaying both a saturated ring and an aromatic moiety in the hydrophobic headgroup of the molecule demonstrate exceptional potency and selectivity for α3β4 nAChRs.

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Information regarding scorpion diversity and their envenoming within Iraq in general, and the Northern Iraq in particular, is limited. The number and distribution of scorpion sting cases and some details of the scorpion fauna of Zakho province were reported for the first time in this study. Overall, 2675 scorpion sting cases were reported between 2008 and 2017 consisting of 1362 male victims (51%) and 1313 female (49%). The highest percentage of victims was between 15 and 49 years old and accounted for 59% of the overall incidence. The highest incidence of scorpion sting cases occurred in the summer, particularly in July when 537 cases were reported. In total, 85 scorpions belonging to two families (Scorpionidae and Buthidae) were captured in the present study. Of the collected samples, Scorpio maurus 47 (55%) was the most abundant followed by Hottentotta saulcyi 28 (33%), and Androctonus crassicauda 10 (12%).