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Peptides from Spider Venoms: A Natural Source of Bioinsecticides

With the increasing global population and decreasing available arable land, there is a burden heavier than ever before on our ability to provide safe, nutritious and sustainable food. Therefore the control of insects, weeds and pathogens that harm agricultural production remains essential.[1,2]Arthropods and insects in particular damage $470 billion-worth of global crop production per year.[3]Annual crop yield lost to insects, currently 18–26% worldwide, is expected to increase in a warming climate.[4]Not only do arthropods threaten food production, they can also act as vectors transmitting deadly diseases.[5] The control of arthropod pests in both the agricultural and public health sector relies primarily on the application of chemical insecticides. Repeated use of commercial products has led to the development and global expansion of pest resistance.[6]Furthermore, there is growing public concern about the potential environmental and long-term human health impacts of certain agrochemicals. Hence, the discovery of selective, effective and environmentally safe agrochemical alternatives to address the pest control challenge remains a necessity.While the crop protection market is dominated by small molecules, new modalities, such as silencing RNA,[7]microbial toxins,[8]and peptidic neurotoxins have received increased attention. Peptides in particular (defined as proteins less than 10 kDa) represent an appealing option as bioinsecticides, due to their potential to be highly potent, while showing exquisite species selectivity. Furthermore, being fully biodegradable into amino acids, peptides guarantee favorable environmental impact. A great natural source of insecticidal peptides are the venoms of insect predators, e.g. spiders, scorpions, centipedes, wasps, predacious mites. Venoms used by insectivores to subjugate their prey are cocktails containing inorganic salts, small molecules such as biogenic amines, peptides and high molecular mass proteins, such as proteases.[9] Of particular interest for crop protection are the venom components that target receptors and ion channels in the insect nervous system.[10,11] An incredibly rich source of such insecticidal neuropeptides are spider venoms. ArachnoServer 3.0, a manually curated database of spider-venom peptides and proteins, contains to date >1500 peptide toxins from 100 spiders.[12] However, only a few are sufficiently potent to warrant consideration as bioinsecticides (i.e. LD50 < 1500 pmol g by injection).[13] In addition to high intrinsic potency, there are several other requirements for a spider-venom peptide to be considered as a bioinsecticide lead, as summarized in Table 1.[14] Selectivity is crucial: ideally, a toxin should target only a narrow range of pest species while not harming vertebrates and other arthropods (e.g. pollinators and natural predators of the target pest species). This is the case of ω-Hexatoxin-Hv1a (ω-HXTXHv1a), a component of the Australian funnel web spider venom and one of the most potent insecticidal peptides known, which is harmless to vertebrates even at very high concentrations.[15] Importantly,ω-HXTX-Hv1a has also been shown to be non-toxic to bees, a strict requirement for modern insecticides.[16] Toxin size/complexity is also critical for bioinsecticide development: the higher the complexity, the more difficult it would be to economically produce large amounts of peptide for agricultural applications. The recent launch of Spear T by the Vestaron Corporation (USA) provides proof-of-concept that spider venom peptides can go all the way to market and be manufactured on a large scale. The active ingredient of Spear T is GS-ω/κ-HXTXHv1a, a spider venom-derived peptide commercialized as bioinsecticide for greenhouse use, targeting a wide range of insects.[17] Nevertheless, with few exceptions, peptidic neurotoxins isolated from spider venoms are generally not orally active on insects. In contrast to most other peptides and proteins, stability is not a concern for these peptides as their particular fold, called a inhibitor cystine knot,[18] provides them with remarkable chemical and thermal stability as well as resistance to proteases.[9] The lack of oral insecticidal activity of venom peptides derives from the limited ability to traverse the gut epithelium to reach the target site, the nerves located in the insect hemocoel (body cavity). Spiders were not under evolutionary pressure to develop orally active peptide toxins, since they inject the venoms directly into the hemocoel of the prey.An array of strategies have been identified to significantly enhance the oral activity of venom peptides, in an attempt to allow their field application (Fig. 1). One option is to modify the peptide chemically. Head-to-tail cyclization of ω-Hexatoxin-Hv1a has been performed in an aim to increase its oral potency, unfortunately without success.[19] Conjugation with polyethylene glycol polymers is another wellestablished approach to modify the properties of a peptide, but has not been applied to spider venom peptides, supposedly beMedicinal Chemistry and Chemical Biology Highlights