Abstract
Drug discovery is an iterative process with high risks and low chance of success. New genomics technologies allow veterinary medicine and agrochemical companies to validate and functionally screen new receptor-based targets, including neuropeptide G-protein coupled receptors, which were previously not amenable to high throughput screening. However this is just the first step in a long process to translate a mechanistic assay hit into a drug on the market. In addition to effectively eradicating pests on crops and parasites on their host, the molecules must also be safe, cheap to synthesise, formulatable and patentable. This is a costly process in which early attrition of unsuitable molecules is key to any successful program. Although first principle discovery is risky the ultimate benefits are considerable and future genomics resources will help to generate higher quality hits to strengthen the discovery pipeline.
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References
Nwaka S, Hudson A. Innovative lead discovery strategies for tropical diseases. Nat Rev Drug Discov 2006; 5:941–955.
Maule A, Geary T, Bowman J et al. Inhibitory effects of nematode fmrfamide-related peptides (farps) on muscle strips from Ascaris suum. Inv Neurosci 1995; 1(3):255–265.
Greenwood K, Williams T, Geary T. Nematode neuropeptide receptors and their development as anthelmintic screens. Parasitology 2005; 131:S169–S177.
Ward E, Bernasconi P. Target-based discovery of crop protection chemicals. Nat Biotech 1999; 7:618–619.
Lee B, Dutton F, Clothier M et al. Synthesis and biological activity of anthelmintic thiadiazoles using an AF-2 receptor binding assay. Bioorg Med Chem Lett 1999; 9:1727–1732.
Hauser F, Williamson M, Cazzamali G et al. Identifying neuropeptide and protein hormone receptors in Drosophila melanogaster by exploiting genomic data. Brief Funct Genomic Proteomic 2006; 4(4):321–330.
Lowery D, Geary T, Kubiak T et al. G-protein coupled receptors and modulators thereof. International Patent 2003; WO 01/38533 A2.
Larsen M, Burton K, Zantello M et al. Type A allatostatins from Drosophila melanogaster and Diplotera puncata activate two Drosophila allatostatin receptors, DAR-1 and DAR-2, expressed in CHO cells. Biochem Biophys Res Comm 2001; 286: 895–901.
Kubiak T, Larsen M, Nulf S et al. Differential activation of “social” and “solitary” variants of the Caenorhabditis elegans G-protein coupled receptor NPR-1 by its cognate ligand AF9. J Biol Chem 2003; 278(36): 33724–33729.
Kubiak T, Larsen M, Zantell M et al. Functional annotation of the putative orphan Caenorhabditis elegans G-protein coupled receptor C10C6.2 as a FLP15 peptide receptor. J Biol Chem 2003; 278(43); 42115–42120.
Minic J, Sautel M, Salesse R et al. Yeast system as a screening tool for pharmacological assessment of G-protein coupled receptors. Curr Med Chem 2005; 12: 961–969.
Thomsen W, Frazer J, Unett D. Functional assays for screening GPCR targets. Curr Opin Biotech 2005; 16:655–665.
Mertens I, Vandingeen A, Meeuen T et al. Functional characterization of the putative orphan neuropeptide G-protein coupled receptor C26F1.6 in Caenorhabditis elegans. FEBS Lett 2004; 573:55–60.
Birse R, Johnson E, Taghert P et al. Widely distributed Drosophila G-protein coupled receptor (CG7887) is activated by endogenous tachykinin-related peptides. J Neurobiol 2005; 66:33–46.
Cismowski M, Takesono A, Ma C et al. Genetic screens in yeast to identify mammalian nonreceptor modulators of G-protein signalling. Nat Biotech 1999; 17(9):878–883.
Wang Z, Broach J, Peiper S. Functional expression of CXCR4 in Saccharomyces cerevisiae in the development of powerful tools for the pharmacological characterization of CXCR4. Meth Mol Biol 2006; 332:115–127.
Wolcke J, Ullmann D. Miniaturized HTS technologies—uHTS. Drug Discov Today 2001; 6(12):637–646.
Sittampalam G, Kahl S, Janzen W. High-throughput screening: advances in assay technologies. Curr Opin Chem Biol 1997; 1:384–391.
Kenny B, Bushfield M, Parry-Smith D et al. The application of high-throughput screening to novel lead discovery. Prog Drug Res 1998; 51:245–269.
Macarron R, Hertzberg R. Design and implementation of high throughput screening assays. Meth Mol Biol 2002; 190:1–29.
Gribbon P, Lyons R, Laflin P et al. Evaluating real-life high-throughput screening data. J Biomol Screen 2005; 10(2):99–107.
Terrett NK, Gardner M, Gordon DW et al. Combinatorial synthesis—the design of compound libraries and their application to drug discovery. Tetrahedron 1995; 51(30):8135–8173.
Feher M, Schmidt JM. Property distributions: differences between drugs, natural products and molecules from combinatorial chemistry. J Chem Inf Comput Sci 2003; 43:218–22.
Becker OM, Shacham S, Marantz Y et al. Modeling the 3D structure of GPCRs: advances and applications to drug discovery. Curr Opin Drug Discov Devel 2003; 6(3):353–361.
Becker OM, Marantz Y, Shacham S et al. G-protein coupled receptors: in silico drug discovery in 3D. PNAS 2004; 101(31): 11304–11309.
Lipinski CA, Lombardo F, Dominy BW et al. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Delivery Rev 1997; 23(1–3):3–25.
Hopkins AL, Groom CR. The druggable genome. Nat Rev Drug Discov 2002; 1(9):727–730.
Walter M. From serendipity to design—making agrochemicals to order. Pesticide Outlook 2003; 14:27–31.
Gilleard JS, Woods DJ, Dow JAT. Model organism genomics in veterinary parasite drug discovery. Trends Parasitol 2005; 21(7):302–305.
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Woods, D., Butler, C., Williams, T., Greenwood, K. (2010). Receptor-Based Discovery Strategies for Insecticides and Parasiticides: A Review. In: Geary, T.G., Maule, A.G. (eds) Neuropeptide Systems as Targets for Parasite and Pest Control. Advances in Experimental Medicine and Biology, vol 692. Springer, Boston, MA. https://doi.org/10.1007/978-1-4419-6902-6_1
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DOI: https://doi.org/10.1007/978-1-4419-6902-6_1
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