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New targets and modes of action for pesticides - PS2127

Description
In spite of the economic importance of beneficial and pest insects, our knowledge of their biology is still far from complete. Recent developments within insect genome projects will, however, have enormous impacts on basic insect science and pest control. The genomes from 24 insect species have recently been sequenced, or are in the process of sequencing, and include those of pest (pea aphid, red flour beetle) and beneficial (honey bee) species. These insect genomic databases are immensely important because they contain the information of all proteins (as their precursor genes), and hence all biochemical and physiological process that occur in an insect.

Currently most insecticides are indiscriminate neurotoxins that are harmful to the environment, hazardous to humans, wildlife and beneficial invertebrates. The need for pesticides with different modes of action is also becoming increasingly important to combat growing problems with resistance and to replace those pesticides that have been removed from the marget.

The insect genome databases will significantly aid in the identification of other insecticide targets, such as cell membrane proteins. One such group are the G-protein coupled receptors (GPCRs), which make up 1-2% of an animals genome. The interaction between GPCRs and the compounds that activate them (e.g. hormones), results in a response leading to a biological effect. These GPCRs modulate virtually all physiological processes in insects, such as reproduction, development, homeostasis and feeding, as well as behaviour. Blocking (with antagonists), or over-stimulating (with agonists), these receptors in pest insects will either kill the animal, or suppress targeted physiological processes reducing their development and reproductive capabilities thereby reducing their populations. The fruit fly (Drosophila melanogaster) genome contains around 160 receptor genes. Similar receptor genes from other insects (eg. aphids, beetles) can also be identified by searching the genome databases.

GPCRs are well-established drug targets, and > 40% of all currently prescribed human medications act on these membrane receptors. High-throughput screening of GPCRs for the presence of agonists or antagonists in large chemical libraries is routinely done in the pharmaceutical industry. Now that specific insect GPCRs have been identified it is feasible that agonists or antagonists to these receptors can be developed which may lead to novel pesticides. Arterra Bioscience, an Italian biotechnology company adapts high-throughput screening technologies to identify chemicals of interest for crop protection.Over the last decade there has been a significant increase in the use of assays to screen for compounds that activate or block GPCRs. These assays also be automated and adapted to microtitre plate formats enabling the screening of a large number of compounds at a time.

The aphid genome database is now available on line and we have been able to identify the genes for the C-type allatostatin and its cognate receptor. Recent studies have demonstrated that when continually fed to the pea aphid, a related peptide (from Lepidoptera) is toxic causing mortality, or retarded growth in surviving aphids compared to controls. The aphid C-type allatostatin is therefore an ideal target for the development of a functional receptor assay.

The primary aims of the proposed project are to assess the potential of insect neuropeptide hormone GPCRs for high-throughput screening assays which will enable the identification of lead compounds for new mode of action pesticides. The specific objectives are:

1. To identify and clone the C-type allatostatin receptor of the pea aphid.

2. To use this to develop a functional receptor assay in collaboration with Dr J Vanden Broeck, Leuven University, Belgium., and to validate the assay in order to assess the potential for development of a high-throughput screening assay
Objective
This is a preliminary project that aims to assess the potential of insect GPCRs for high throughput screening assays that could be used to identify lead compounds for new mode of action pesticides through the following objectives.
1. Probe the Tribolium castaneum and/or Acyrthosiphon pisum genomes for GPCRs genes and identify GPCRs involved in specific physiological processes (moulting, reproduction, osmoregulation).
2. Develop a functional assay to a known insect neuropeptide GPCR (eg C-type allatostatin receptor of Pea Aphid).
3.Use the outcomes of this project for a follow on study to develop high throughput screening assays for insect GPCRs.

The primary aims of the proposed work are to assess the potential of insect neuropeptide hormone GPCRs for high-throughput screening assays which will enable the identification of lead compounds for new mode of action pesticides. The specific objectives are:

1. To identify and clone (i.e. replicate) a complimentary DNA (cDNA) sequence equivalent to the protein coding region of the C-type allatostatin GPCR gene.

2. To use this to develop a functional assay to an insect hormone GPCR in collaboration with Dr J Vanden Broeck, Leuven University, Belgium., and to validate the assay using one or more potential ligands (hormones) in order to assess the potential for development of a high-throughput assay

The project is based on a one-year work plan.
Project Documents
• Final Report : New Targets and Modes of Action for Pesticides   (211k)
Time-Scale and Cost
From: 2009

To: 2009

Cost: £75,580
Contractor / Funded Organisations
Central Science Laboratory
Keywords
Application              
Biopesticide              
Genomics              
Insecticide use              
Natural              
Pest and Weed Control              
Pest Control              
Pesticide use              
Pesticides              
Plant health              
Plants and Animals              
Fields of Study
Pesticide Safety