Allosteric modulators of ligand-gated ion channels as insecticides with novel modes of action

The focus of this LIDo CASE studentship proposal is to examine allosteric modulation of insect ligand-gated
ion channels (LGICs), with the aim of evaluating the hypothesis that this may provide an opportunity to develop new insecticides with novel modes of action. Importantly, this proposal addresses one of the BBSRC's key strategic priorities: 'Agriculture and Food Security'.
Insecticides provide an important mechanism for controlling insect pests that might otherwise cause devastating damage to food crops. Currently an issue of major concern is the increasing problem of insects developing resistance to existing classes of insecticides. Frequently resistance occurs as a consequence of insects developing more efficient ways to inactivate insecticides (detoxification mechanisms) but resistance can also arise as a result of new mutations appearing within the protein that the insecticide binds to. Both mechanisms result in insecticides becoming less effective. As a consequence of these problems associated with insecticide resistance there is an increasing and urgent need for new types of insecticides with novel mechanisms of action. Many of the most effective insecticides act as activators or inhibitors of receptors and ion channels in the insect nervous system. Our focus in this research proposal is a group of neurotransmitter receptors that act as LGICs that are known to be effective targets for existing insecticides. Our aim is to identify compounds that modulate the properties of these receptors but do so by binding to an allosteric site. In addition, our aim is to identify allosteric modulators that act at sites that are distinct from existing classes of insecticide. Our rationale is that such allosteric modulators may have insecticidal activity but may be unaffected by existing mechanisms of resistance.
We will build on our recent research that has resulted in the identification of novel binding sites on mammalian LGICs. Our aim will be to develop compounds that interact with similar sites on insect LGICs. Many compounds acting on LGICs (both therapeutically useful drugs and insecticides) bind to the orthosteric neurotransmitter-binding site. However, because this binding site is essential to the normal functioning of these receptors, this site tends to be highly conserved between different species. In contrast, allosteric sites can (and do) show much considerably greater diversity between receptor subtypes and between different species. By focusing on the development and characterisation of allosteric modulators of insect LGICs, our longer-term goal is to identify compounds with potential insecticidal activity that also have greater species-selectivity. Our approach will be to focus on a subset of insect receptors for acetylcholine, gamma-aminobutyric acid (GABA) and glutamate. These will also be modelled structurally based on homology to recent high-resolution atomic structures to allow in silico rational drug discovery. Critically, we have selected LGICs that are already validated targets for insecticides. However they are also receptors for which (based on studies of their mammalian homologues), we expect to be capable of modulation via

allosteric binding sites. Our studies will focus primarily upon studies of cloned receptors but will be complemented by studies with native receptors and insect bioassays (using techniques and facilities that are available at the industrial partner, Syngenta).