Technology
Exploiting Discoveries
The novel active sites for spider venom peptides are actually protein receptors that are positioned in cell membranes. These receptors serve as the gateway for essential metabolic functions, such as allowing ions like calcium and potassium to enter cells in order to maintain a well-functioning nervous system. When a receptor is blocked by an SV peptide, the metabolic pathway shuts down, nervous system activity ceases and the insect dies. Using the SV peptides themselves as "bait", scientists were able to isolate and identify the nerve cell-based receptors for the SV peptides. Two of these receptors are voltage-gated calcium channel receptors and the third is a calcium-activated potassium channel receptor. These receptors are now being employed in several ways by Vestaron to identify additional pesticide compounds.
In the first approach, the three receptors have been incorporated into high-throughput screens that are being used to screen libraries of potential, small-molecule, chemical insecticides that mimic the insecticidal properties of the SV peptides. In this work, Vestaron scientists are using "competitive" assays, in which the SV peptide and the chemical from the library compete for the same active site on the receptor. This insures the chemical's binding site is the same as the SV peptide and eliminates false positives – chemicals that bind to the wrong place on a receptor. Non-specific binding to receptors is often the source of the unwanted toxicity exhibited by pesticides.
In the second approach, researchers examined the SV peptide-receptor complex and determined its three-dimensional structure. The specific site of the interaction between the SV peptide and receptor (called a pharmacophore) was then mapped. Knowledge of the pharmacophore structure is being used to "rationally design" compounds that also will mimic the action of the SV peptide. This so-called "in silco" computerized design technology has produced several synthetic compounds that exhibit activity at the new target site.