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Prospects for rational approaches to anthelmintic discovery

Published online by Cambridge University Press:  06 April 2009

D. P. Thompson ,
R. D. Klein  and
T. G. Geary
D. P. Thompson*
Affiliation:
Animal Health Discovery Research, Mailstop 7923-25-13, Pharmacia & Upjohn, Co., 301 Henrietta Street, Kalamazoo, MI 49001, USA
R. D. Klein
Affiliation:
Animal Health Discovery Research, Mailstop 7923-25-13, Pharmacia & Upjohn, Co., 301 Henrietta Street, Kalamazoo, MI 49001, USA
T. G. Geary
Affiliation:
Animal Health Discovery Research, Mailstop 7923-25-13, Pharmacia & Upjohn, Co., 301 Henrietta Street, Kalamazoo, MI 49001, USA
*
*Corresponding author.
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Summary

Rational approaches to anthelmintic discovery include the design of screens for compounds directed at specific proteins in helminths that are pharmacologically distinguishable from their vertebrate homologues. The existence of several anthelmintics that selectively target the neuromusculature of helminths (e.g. levamisole, ivermectin, praziquantel, metrifonate), together with recent basic research in helminth physiology, have contributed to the recognition that neurobiology distinguishes these organisms from their vertebrate hosts. In this survey, we focus on mechanism-based screening and its application to anthelmintic discovery, with particular emphasis on targets in the neuromusculature of helminths. Few of these proteins have been exploited in chemotherapy. However, recent studies in comparative pharmacology and molecular biology, including the C. elegans genome project, have provided insights on potential new targets and, in some cases, molecular probes useful for their incorporation in mechanism-based screens.

Keywords

Rational drug discoverymechanism-based screenshigh-throughput screenscomparative neuropharmacologyneuroreceptorsnutrient-dependent viability assay
Type
Research Article
Information
Parasitology , Volume 113 , supplement S1: Molecular biochemistry and physiology of helminth neuromuscular systems , January 1996 , pp. S217 - S238
Copyright
Copyright © Cambridge University Press 1996

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References

REFERENCES

Albrecht, S. & Walter, R. D. (1991). Hallucinogenic and neuroleptic drug interactions with potential neurotransmitter receptors in parasitic nematodes. Molecular and Biochemical Parasitology 45, 289–96.CrossRefGoogle ScholarPubMed
Angelo, M., Ortwine, D., Worth, D., Werbel, L. M. & McCall, J. W. (1983). Synthesis and antifilarial activity of JV-[4-[[4-alkoxy-3-[(dialkylamino) methyl]phenyl]arnino]-2-pyrimidinyl]-N′-phenylguanidines. Journal of Medicinal Chemistry 26, 1258–67.CrossRefGoogle Scholar
Arena, J. P., Liu, K. K., Paress, P., Frazier, E. G., Cully, D. F., Mrozik, H. & Schaeffer, J. M. (1995). The mechanism of action of avermectins in Caenorhabditis elegans: correlation between activation of glutamatesensitive chloride current, membrane binding, and biological activity. Journal of Parasitology 81, 286–94.CrossRefGoogle ScholarPubMed
Ashton, F. T. & Schad, G. A. (1996). Amphids in Strongyloides stercoralis and other parasitic nematodes. Parasitology Today 12, 187–94.CrossRefGoogle ScholarPubMed
Atchison, W. D., Geary, T. G., Manning, B., Vandewaa, E. A. & Thompson, D. P. (1992). Comparative neuromuscular blocking actions of levamisole and pyrantel-type anthelmintics on rat and gastrointestinal somatic muscle. Toxicology and Applied Pharmacology 112, 133–42.CrossRefGoogle ScholarPubMed
Avery, L. (1993). Motor neuron M3 controls pharyngeal muscle relaxation timing in Caenorhabditis elegans. Journal of Experimental Biology 175, 283–97.CrossRefGoogle ScholarPubMed
Avery, L. & Horvitz, H. R. (1989). Pharyngeal pumping continues after laser killing of the pharyngeal nervous system of C. elegans. Neuron 3, 473–85.CrossRefGoogle ScholarPubMed
Avery, L. & Horvitz, H. R. (1990). Effects of starvation and neuroactive drugs on feeding in Caenorhabditis elegans. Journal of Experimental Zoology 253, 263–70.CrossRefGoogle ScholarPubMed
Avery, L.., Lockery, S. & Raizen, D. (1995). Electrophysiological methods. In Methods in Cell Biology, volume 48; C. elegans: modern biological analysis of an organism (ed. Epstein, H. F. & Shakes, D. C.), pp. 251–69. San Diego, CA: Academic Press.Google Scholar
Ballivet, M.Alliod, C., Bertrand, S. & Bertrand, D. (1996). Nicotinic acetylcholine receptors in the nematode Caenorhabditis elegans. Journal of Molecular Biology 258, 261–9.CrossRefGoogle ScholarPubMed
Bargmann, C. I. & Horvitz, H. R. (1991). Chemosensory neurons with overlapping functions: direct chemotaxis to multiple chemicals in C. elegans. Neuron 7, 729–42.CrossRefGoogle ScholarPubMed
Bargmann, C. I., Thomas, J. H. & Horvitz, H. R. (1990). Chemosensory cell function in the behavior and development of Caenorhabditis elegans. Cold Spring Harbor Symposia on Quantitative Biology 5, 529–38.CrossRefGoogle Scholar
Bascal, Z., Holden-Dye, L., Willis, R. J., Smith, S. W. G. & Walker, R. J. (1996). Novel azole derivatives are antagonists at the inhibitory GABA receptor on the somatic muscle cells of the parasitic nematode Ascaris suum. Parasitology 112, 253–9.CrossRefGoogle ScholarPubMed
Blair, K. L., Bennett, J. L. & Pax, R. A. (1993). Serotonin and acetylcholine: modulation of praziquantel-induced contraction of magnesium paralyzed Schistosoma mansoni. Journal of Experimental Biology 185, 267–8.CrossRefGoogle Scholar
Bottjer, K. P. & Bone, L. W. (1985). Trichostrongylus colubriformis: effect of anthelmintics on ingestion and oviposition. International Journal for Parasitology 15, 501–3.CrossRefGoogle ScholarPubMed
Bowman, J. W., Winterrowd, C. A., Friedman, A. R., Thompson, D. P., Klein, R. D., Davis, J. P., Maule, A. G., Blair, K. L. & Geary, T. G. (1995). Nitric oxide mediates the inhibitory effects of SDPNFLRFamide, a nematode FMRFamide-related neuropeptide, in Ascaris suum. Journal of Neurophysiology 74, 1880–8.CrossRefGoogle ScholarPubMed
Brann, M. R., Messier, T., Dorman, C. & Lannigan, D. (1996). Cell-based assays for G-proteincoupled/tyrosine kinase-coupled receptors. Journal of Biomolecular Screening 1, 43–5.CrossRefGoogle Scholar
Browne, M. J. & Balcarek, J. M. (1993). Expression of mammalian cell-surface receptors in higher eukaryotic systems. Current Opinion in Biotechnology 4, 53–7.CrossRefGoogle ScholarPubMed
Brownlee, D. J. A., Fairweather, I., Johnston, C. F. & Shaw, C. (1994). Immunocytochemical demonstration of peptidergic and serotonergic components in the enteric nervous system of the roundworm Ascaris suum (Nematoda, Ascarideae). Parasitology 108, 89–105.CrossRefGoogle Scholar
Brownlee, D. J. A., Holden-Dye, L., Fairweather, I. & Walker, R. J. (1995). The action of serotonin and the nematode neuropeptide KSAYMRFamide on the pharyngeal muscle of the parasitic nematode, Ascaris suum. Parasitology 111, 379–84.CrossRefGoogle ScholarPubMed
Bunin, B. A., Plunkett, M. J. & Ellman, J. A. (1994). The combinatorial synthesis and chemical and biological evaluation of a 1,4-benzodiazepine library. Proceedings of the National Academy of Sciences, USA 91, 4708–12.CrossRefGoogle Scholar
Burch, R. M. & Kyle, D. J. (1991). Mass receptor screening for new drugs. Pharmaceutical Research 8, 141–7.CrossRefGoogle ScholarPubMed
Burnbaum, J. J., Ohlmeyer, M. H. J., Reader, J. C., Henderson, I., Dillard, L. W., Li, G., Randle, T. L., Sigal, N. H., Chelsky, D. & Baldwin, J. J. (1995). A paradigm for drug discovery employing encoded combinatorial libraries. Proceedings of the National Academy of Sciences, USA 92, 6027–31.CrossRefGoogle Scholar
Camacho, M. & Agnew, A. (1995). Schistosoma: rate of glucose import is altered by acetylcholine interaction with tegumental acetylcholine receptors and acetylcholinesterase. Experimental Parasitology 81, 584–91.CrossRefGoogle ScholarPubMed
Camacho, M., Alsford, S., Jones, A. & Agnew, A. (1995). Nicotinic acetylcholine receptors on the surface of the blood fluke Schistosoma. Molecular and Biochemical Parasitology 71, 127–34.CrossRefGoogle ScholarPubMed
Camacho, M., Tarrab-Hazdai, R., Espinoza, B., Arnon, R. & Agnew, A. (1994). The amount of acetylcholinesterase on the parasite surface reflects the differential sensitivity of schistosome species to metrifonate. Parasitology 108, 153–60.CrossRefGoogle ScholarPubMed
Chaudhuri, J. & Donahue, M. J. (1989). Serotonin receptors in the tissues of adult Ascaris suum. Molecular and Biochemical Parasitology 35, 191–8.CrossRefGoogle ScholarPubMed
Chen, W., Terada, M. & Cheng, J. T. (1996). Characterization of subtypes of gamma-aminobutyric acid receptors in an Ascaris muscle preparation by binding assay and binding of PF1022A, a new anthelmintic, on the receptors. Parasitology Research 82, 97–101.CrossRefGoogle Scholar
Christ, D., Oh, J. & Saz, H. J. (1994). Contractions of the filariid Acanthocheilonema viteae induced by potassium chloride. Parasitology Research 80, 449–53.CrossRefGoogle ScholarPubMed
Christ, D. & Stillson, T. (1992). Effects of calcium channel blockers on the contractility of the filariid Acanthocheilonema viteae. Parasitology Research 78, 489–94.CrossRefGoogle ScholarPubMed
Colman, P. M. (1995). Structure-based drug design. Current Opinion in Structural Biology 4, 868–74.CrossRefGoogle Scholar
Colquhoun, L. M., Holden-Dye, L. & Walker, R. J. (1991). The pharmacology of cholinoceptors on the somatic muscle cells of the parasitic nematode Ascaris suum. Journal of Experimental Biology 158, 509–30.CrossRefGoogle ScholarPubMed
Colquhoun, L. M., Holden-Dye, L. & Walker, R. J. (1993). The action of nicotinic receptor specific toxins on the somatic muscle cells of the parasitic nematode Ascaris suum. Molecular Neuropharmacology 3, 11–16.Google Scholar
Conder, G. A., Johnson, S. S., Nowakowski, D. S., Dutton, F. E., Nelson, S. J., Thomas, E. M., Davis, J. P. & Thompson, D. P. (1995). Anthelmintic profile of the cyclodepsipeptide PF1022A in in vitro and in vivo models. Journal of Antibiotics 48, 820–3.CrossRefGoogle ScholarPubMed
Cully, D. F., Vassilatis, D. K., Liu, K. K., Paress, P. S., Van Der Ploeg, L. H. T., Schaeffer, J. M. & Arena, J. P. (1994). Cloning of an avermectin-sensitive glutamategated chloride channel from Caenorhabditis elegans. Nature 371, 707–11.CrossRefGoogle ScholarPubMed
Culotti, J. G. & Klein, W. L. (1983). Occurrence of muscarinic acetylcholine receptors in wild type and cholinergic mutants of Caenorhabditis elegans. Journal of Neuroscience 3, 359–68.CrossRefGoogle ScholarPubMed
Day, T. A., Bennett, J. L. & Pax, R. A. (1992). SchistOSOma mansoni: patch-clamp study of a nonselective cation channel in the outer tegumental membrane of females. Experimental Parasitology 74, 348–56.CrossRefGoogle ScholarPubMed
Day, T. A., Bennett, J. L. & Pax, R. A. (1993). Voltagegated currents in muscle cells of Schistosoma mansoni. Parasitology 106, 471–7CrossRefGoogle ScholarPubMed
De Clerq, E. (1993). HIV-1-specific RT inhibitors: highly selective inhibitors of human immunodeficiency virus type 1 that are specifically targeted at the viral reverse transcriptase. Medicinal Research Reviews 13, 229–58.CrossRefGoogle Scholar
De Mello, W. C. & Tercaffs, R. R. (1966). Ionic permeability of the ‘;Ascaris’ body wall. Ada Physiology of Latin America 16, 121–7.Google ScholarPubMed
De Vries, D. J. & Beart, P. M. (1995). Fishing for drugs from the sea: status and strategies. Trends in Pharmacological Sciences 16, 275–9.CrossRefGoogle ScholarPubMed
De Witt, S. H., Kiely, J. S., Stankovic, C. J., Schroeder, M. C., Cody, D. M. R. & Pavia, M. R. (1993). “Diversomers”: an approach to nonpeptide, nonoligomeric chemical diversity. Proceedings of the National Academy of Sciences, USA 90, 6909–13.CrossRefGoogle ScholarPubMed
Donahue, M. J., Yacoub, N. J., Michnoff, C. A., Masaracchia, R. A. & Harris, B. G. (1981). Serotonin (5-hydroxytryptamine): a possible regulator of glycogenolysis in perfused muscle segments of Ascaris suum. Biochemical and Biophysical Research Communications 101, 112–7.CrossRefGoogle ScholarPubMed
Duittoz, A. H. & Martin, R. J. (1990). Effects of the arylaminopyridazine-GABA derivatives, SR951O3 and SR9531 on the Ascaris muscle GABA receptor: the relative potency of the antagonists in Ascaris is different to that at vertebrate GABAA receptors. Comparative Biochemistry and Physiology 98C, 417–22.Google Scholar
Eakin, A. E., Nieves-Alicea, R., Tosado-Acevedo, R., Chin, M. S., Wang, C. C. & Craig, S. P. III.,. (1995). Comparative complement selection in bacteria enables screening for lead compounds targeted to a purine salvage enzyme of parasites. Antimicrobial Agents and Chemotherapy 39, 620–5.CrossRefGoogle ScholarPubMed
Elion, G. B. (1989). The purine path to chemotherapy. Science 244, 41–7.CrossRefGoogle ScholarPubMed
Endo, A. (1992). The discovery and development of HMG-CoA reductase inhibitors. Journal of Lipid Research 33, 1569–82.CrossRefGoogle ScholarPubMed
Eriksson, K. S., Maule, A. G., Halton, D. W., Panula, P. A. J. & Shaw, C. (1995). GABA in the nervous system of parasitic flatworms. Parasitology 110, 339–46.CrossRefGoogle ScholarPubMed
Evans, B. E., Rittle, K. E., Bock, M. G., Dipardo, R. M., Freidinger, R. M., Whitter, W. L., Lundell, G. F., Veber, D. F., Anderson, P. S., Chang, R. S. L., Lotti, V. J., Cerino, D. J., Chen, T. B., Kling, P. J., Kunkel, K. A., Springer, J. P. & Hirshfield, J. (1988). Methods for drug discovery: development of potent, selective, orally effective cholecystokinin antagonists. Journal of Medicinal Chemistry 31, 2235–46.CrossRefGoogle ScholarPubMed
Fields, S. & Song, O.-K. (1989). A novel genetic system to detect protein-protein interactions. Nature 340, 245–6.CrossRefGoogle ScholarPubMed
Foster, N. & Lee, D. L. (1996). A vasoactive intestinal polypeptide-like protein excreted/secreted by Nippostrongylus brasiliensis and its effect on contraction of uninfected rat intestine. Parasitology 112, 97–104.CrossRefGoogle ScholarPubMed
Fuller, R. W. & Steranka, L. R. (1987). Drug discovery at the enzyme level. In Drug Discovery and Development (ed. Williams, M. & Malick, J. B.), pp. 177–98. Clifton, NJ: The Humana Press.CrossRefGoogle Scholar
Geary, T. G., Blair, K. L., Ho, N. F. H., Sims, S. M. & Thompson, D. P. (1995 a). Biological functions of nematode surfaces. In Molecular Approaches to Parasitology (ed. Boothroyd, J. C. & Komuniecki, R.), pp. 57–76. New York, NY: Wiley-Liss.Google Scholar
Geary, T. G., Bowman, J. W., Friedman, A. R., Maule, A. G., Davis, J. P., Winterrowd, C. A., Klein, R. D. & Thompson, D. P. (1995 b). The pharmacology of FMRFamide-related neuropeptides in nematodes: new opportunities for rational anthelmintic discovery? International Journal for Parasitology 25, 1273–80.CrossRefGoogle ScholarPubMed
Geary, T. G., Divo, A. A. & Jensen, J. B. (1986). Effect of calmodulin inhibitors on viability and mitochondrial potential of Plasmodium falciparum in culture. Antimicrobial Agents and Chemotherapy 30, 785–8.CrossRefGoogle ScholarPubMed
Geary, T. G., Klein, R. D., Vanover, L., Bowman, J. W. & Thompson, D. P. (1992). The nervous systems of helminths as targets for drugs. Journal of Parasitology 78, 215–30.CrossRefGoogle ScholarPubMed
Geary, T. G., Sims, S. M., Thomas, E. M., Vanover, L.Davis, J. P., Winterrowd, C. A., Klein, R. D., Ho, N. F. H. & Thompson, D. P. (1993 a). Haemonchus contortus: ivermectin-induced paralysis of the pharynx. Parasitology 77, 88–96.Google Scholar
Geary, T. G., Winterrowd, C. A., Alexander-Bowman, S. J., Favreau, M. A., Nulf, S. C. & Klein, R. D. (1993 b). Ascaris suum: cloning of a cDNA encoding phosphoenolpyruvate carboxykinase. Experimental Parasitology 77, 15–61.CrossRefGoogle ScholarPubMed
Gill, J. H. & Lacey, E. (1993). In vitro activity of paraherquamide against the free-living stages of Haemonchus contortus, Trichostrongylus colubriformis and Ostertagia circumcincta. International Journal for Parasitology 23, 375–81.CrossRefGoogle ScholarPubMed
Gordon, E. M., Barrett, R. W., Dower, W. J., Fodor, S. P. & Gallop, M. A. (1994). Applications of combinatorial technologies to drug discovery. 2. Combinatorial organic synthesis, library screening strategies, and future directions. Journal of Medicinal Chemistry 37, 1385–401.CrossRefGoogle ScholarPubMed
Greer, J., Erickson, J. W., Baldwin, J. J. & Varney, M. D. (1994). Application of the three-dimensional structures of protein target molecules in structurebased drug design. Journal of Medicinal Chemistry 37, 1035–54.CrossRefGoogle ScholarPubMed
Halton, D. W., Shaw, C., Maule, A. G. & Smart, D. (1994). Regulatory peptides in helminth parasites. Advances in Parasitology 34, 163–227.CrossRefGoogle ScholarPubMed
Hawdon, J. & Schad, G. A. (1990). Serum-stimulated feeding in vitro by infective larvae of the hookworm Ancylostoma caninum. Journal of Parasitology 76, 394–8.CrossRefGoogle ScholarPubMed
Hodgkin, J., Plasterk, R. H. A. & Waterston, R. H. (1995). The nematode Caenorhabditis elegans and its genome. Science 270, 410–4.CrossRefGoogle ScholarPubMed
Jeansonne, N. E. (1994). Yeast as a model system for mammalian seven-transmembrane segment receptors. Proceedings of the Society for Experimental Biology and Medicine 206, 35–44.CrossRefGoogle Scholar
Johnson, C. D., Reinitz, C. A., Sithigorngul, P. & Stretton, A. O. W. (1996). Neuronal localization of serotonin in the nematode Ascaris suum. Journal of Comparative Neurology 367, 352–60.3.0.CO;2-4>CrossRefGoogle ScholarPubMed
Jones, S. J. M. & Baillie, D. L. (1995). Characterization of the let-653 gene in Caenorhabditis elegans. Molecular and General Genetics 248, 719–26.CrossRefGoogle ScholarPubMed
Kadam, S., Poddig, J., Humphrey, P., Karwowski, J., Jackson, M., Tennant, S., Fung, L., Hochlowski, J., Rasmussen, R. & Mcalpine, J. (1994). Citrinin hydrate and radicinin: human rhinovirus 3C-protease inhibitors discovered in a target-directed microbial screen. Journal of Antibiotics 47, 836–9.CrossRefGoogle Scholar
Kaneto, R., Kojima, I., Shibamoto, N., Nishida, H., Okamoto, R., Akagawa, R. & Mizuno, S. (1994). A rapid and simple screening method for HIV-1 protease inhibitors using recombinant Escherichia coli. Journal of Antibiotics 47, 492–5.CrossRefGoogle ScholarPubMed
Kim, E., Day, T. A., Bennett, J. L., & Pax, R. A. (1995 a ). Cloning and functional expression of a Shaker-related voltage-gated potassium channel gene from Schistosoma mansoni (Trematoda: Digenea). Parasitology 110, 171–80.CrossRefGoogle ScholarPubMed
Kim, E., Day, T. A., Marks, N. J., Johnston, R. N., Halton, D. W., Shaw, C., Chen, G.-Z., Bennett, J. L. & Pax, R. A. (1995 b). Immunohistochemical localization of a Shaker- related voltage-gated potassium channel protein in Schistosoma mansoni (Trematoda: Digenea). Experimental Parasitology 81, 421–9.CrossRefGoogle Scholar
Kirsch, D. R. (1993). Development of improved cellbased assays and screens in Saccharomyces through the combination of molecular and classical genetics. Current Opinion in Biotechnology 4, 543–52.CrossRefGoogle ScholarPubMed
Kivlighn, S. D., Huckle, W. R., Zingaro, G. J., Rivero, R. A., Lotti, V. J., Chang, R. S. L., Schorn, T. W., Kevin, N., Johnson, R. G. Jr., Greenlee, W. J. & Siegl, P. K. S. (1995). Discovery of L-162,313: a nonpeptide that mimics the biological actions of angiotensin II. American Journal of Physiology 268, R820–3.Google ScholarPubMed
Klein, R. D. & Geary, T. G. (1992). Method of identifying compounds useful as antiparasitic drugs. United States Patent No. 5,079,143.Google Scholar
Klein, R. D., Olson, E. R., Favreau, M. A., Winterrowd, C. A., Hatzenbuhler, N. T., Shea, M. H., Nulf, S. C. & Geary, T. G. (1991). Cloning of a cDNA encoding phosphofructokinase from Haemonchus contortus. Molecular and Biochemical Parasitology 48, 17–26.CrossRefGoogle ScholarPubMed
Klein, R. D., Winterrowd, C. A., Hatzenbuhler, N. T., Shea, M. H., Favreau, M. A., Nulf, S. C. & Geary, T. G. (1992). Cloning of a cDNA encoding phosphoenolpyruvate carboxykinase from Haemonchus contortus. Molecular and Biochemical Parasitology 50, 285–94.CrossRefGoogle ScholarPubMed
Knox, D. P. (1994). Parasite enzymes and the control of roundworm and fluke infestation in domestic animals. British Veterinary Journal 150, 319–37.CrossRefGoogle ScholarPubMed
Kuntz, I. D. (1992). Structure-based strategies for drug design and discovery. Science 257, 1078–82.CrossRefGoogle ScholarPubMed
Lange, A.B, Orchard, I., Wang, Z. & Nachman, R. J. (1995). A nonpeptide agonist of the invertebrate receptor for SchistoFLRFamide (PDVDHVFLRFamide), a member of a subfamily of insect FMRFamide-related peptides. Proceedings of the National Academy of Sciences, USA 92, 9250–3.CrossRefGoogle ScholarPubMed
Laughton, D. L., Amar, M., Thomas, P., Towner, P., Harris, P., Lunt, G. G. & Wolstenholme, A. J. (1994). Cloning of a putative inhibitory amino acid receptor subunit from the parasitic nematode Haemonchus contortus. Receptors and Channels 2, 155–63.Google ScholarPubMed
Laughton, D. L., Wheeler, S. V., Lunt, G. G. & Wolstenholme, A. J. (1995). The β-subunit of the Caenorhabditis elegans avermectin receptor responds to glycine and is encoded by chromosome 1. Journal of Neurochemistry 64, 2354–7.CrossRefGoogle ScholarPubMed
Lewis, J. A., Fleming, J. T., McLafferty, S., Murphy, H. & Wu, C. (1987). The levamisole receptor, a cholinergic receptor of the nematode Caenorhabditis elegans. Molecular Pharmacology 31, 185–93.Google ScholarPubMed
Lingueglia, E., Champigny, G., Lazdunski, M. & Barbry, P. (1995). Cloning of the amiloride-sensitive FMRFamide peptide-gated sodium channel. Nature 378, 730–3.CrossRefGoogle ScholarPubMed
Luyten, W. H. M. L. & Leysen, J. E. (1993). Receptor cloning and heterologous expression – towards a new tool for drug discovery. Trends in Biotechnology 11, 247–53.CrossRefGoogle ScholarPubMed
Ma, J. & Ptashne, M. (1987). Deletion analysis of GAL4 defines two transcription activating segments. Cell 48, 847–53.CrossRefGoogle ScholarPubMed
Mansour, T. (1984). Serotonin receptors in parasitic worms. Advances in Parasitology 23, 1–36.Google ScholarPubMed
Martin, R. J. (1993). Neuromuscular transmission in nematode parasites and antinematodal drug action. Pharmacology and Therapeutics 58, 13–50.CrossRefGoogle ScholarPubMed
Martin, R. J. (1996). An electrophysiological preparation of Ascaris suum pharyngeal muscle reveals a glutamate-gated chloride channel sensitive to the avermectin analogue, milbemycin D. Parasitology 112, 247–52.CrossRefGoogle Scholar
Masler, E. P., Kelly, T. J. & Menn, J. J. (1993). Insect neuropeptides: discovery and application in insect management. Archives of Insect Biochemistry and Physiology 22, 87–111.CrossRefGoogle ScholarPubMed
Maule, A. G., Geary, T. G., Bowman, J. W., Marks, N. J., Blair, K. K., Halton, D. W., Shaw, C. & Thompson, D. P. (1995). Inhibitory effects of nematode FMRFamide-related peptides (FaRPs) on muscle strips from Ascaris suum. Invertebrate Neuroscience 1, 25–65.CrossRefGoogle ScholarPubMed
Maule, A. G., Geary, T. G., Marks, N. J., Bowman, J. W., Friedman, A. R. & Thompson, D. P. (1996). Nematode FMRFamide-related peptide (FaRP)-systems and rational drug discovery. International Journal for Parasitology (in press).CrossRefGoogle Scholar
McKerrow, J. H. (1994). Cysteine proteases of parasites: a remarkable diversity of function. Perspectives in Drug Discovery and Design 2, 437–44.CrossRefGoogle Scholar
McKerrow, J. H., Newport, G. & Fishelson, Z. (1991). Recent insights into the structure and function of a larval proteinase involved in host infection by a multicellular parasite. Proceedings of the Society for Experimental Biology and Medicine 197, 119–24.CrossRefGoogle ScholarPubMed
Mendel, J. E., Korswagen, H. C., Liu, K. S., Hajducronin, Y. M., Simon, M. I., Plasterk, R. H. A. & Sternberg, P. W. (1995). Participation of the protein Go in multiple aspects of behavior in C. elegans. Science 267, 1652–5.CrossRefGoogle ScholarPubMed
Mihara, S.-I., Hara, M., Nakamura, M., Sakurawi, K., Tokura, K., Fujimoto, M., Fukai, T. & Nomura, T. (1995). Non-peptide bombesin receptor antagonists, kuwanon G and H, isolated from mulberry. Biochemical and Biophysical Research Communications 213, 594–9.CrossRefGoogle Scholar
Omura, S. (1986). Philosophy of new drug discovery. Microbiological Reviews 50, 259–79.CrossRefGoogle ScholarPubMed
Omura, S. (1992). The expanded horizon for microbial metabolites – a review. Gene 115, 141–9.CrossRefGoogle ScholarPubMed
Ostlind, D. A., Mickle, W. G., Ewaniw, D. V., Andriuli, F. J., Campbell, W. C.Hernandez, S., Mochales, S. & Munguira, E. (1990). Efficacy of paraherquamide against immature Trichostrongylus colubriformis in the gerbil (Meriones unguiculatas). Research in Veterinary Science 48, 260–1.CrossRefGoogle Scholar
Ozenberger, B. A. & Young, K. H. (1995). Functional interaction of ligands and receptors of the hematopoietic superfamily in yeast. Molecular Endocrinology 9, 1321–9.Google ScholarPubMed
Patel, A., Smith, H. J. & Sewell, R. D. (1993). Inhibitors of enkephalin-degrading enzymes as potential therapeutic agents. Progress in Medicinal Chemistry 30, 327–78.CrossRefGoogle ScholarPubMed
Pax, R. A. & Bennett, J. L. (1991). Neurobiology of parasitic helminths: possible solutions to the problems of correlating structure with function. Parasitology 102, S31–9.CrossRefGoogle Scholar
Pax, R. A., Fetterer, R. H. & Bennett, J. L. (1979). Effects of fluoxetine and imipramine on male Schistosoma mansoni. Comparative Biochemistry and Physiology 64C, 123–7.Google ScholarPubMed
Pax, R. A., Geary, T. G., Bennett, J. L. & Thompson, D. P. (1995). Ascaris suum: characterization of transmural and hypodermal potentials. Experimental Parasitology 80, 85–97.CrossRefGoogle ScholarPubMed
Pennypacker, K. R. (1995). Pharmacological regulation of transcription factor binding. Pharmacology 51, 1–12.CrossRefGoogle ScholarPubMed
Plasterk, R. H. A. (1995). Reverse genetics: from gene sequence to mutant worm. In Methods in Cell Biology, volume 48; Caenorhabditis elegans: modern biological analysis of an organism, (ed. Epstein, G. F. & Shakes, D. C.), pp. 59–80. San Diego, CA: Academic Press.Google Scholar
Plasterk, R. H. A. (1996). Postsequence genetics of Caenorhabditis elegans. Genome Research 6, 169–75.CrossRefGoogle ScholarPubMed
Pleiss, U., Harder, A., Turberg, A., Londershausen, M., Iinuma, K., Mencke, N., Jeschke, P. & Bonse, G. (1995). Synthesis of a radiolabeled cyclodepsipeptide [3H-methyl]PF1022A. Journal of Labelled Compounds and Radiopharmaceuticals 38, 61–9.3.0.CO;2-8>CrossRefGoogle Scholar
Potenza, M. N., Graminski, G. F. & Lerner, M. R. (1992). A method for evaluating the effects of ligands upon Gs protein-coupled receptors using a recombinant melanophore-based bioassay. Analytical Biochemistry 206, 315–22.CrossRefGoogle ScholarPubMed
Rabbi, L. E., Russek, S. J. & Farb, D. H. (1995). From ion currents to genomic analysis-recent advances in GABAA receptor research. Synapse 21, 189–274.Google Scholar
Raizen, D. M. & Avery, L. (1994). Electrical activity and behavior in the pharynx of Caenorhabditis elegans. Neuron 12, 483–95.CrossRefGoogle ScholarPubMed
Rand, J. B. & Johnson, C. D. (1995). Genetic pharmacology: interactions between drugs and gene products in Caenorhabditis elegans. In Methods in Cell Biology, volume 48; Caenorhabditis elegans: modern biological analysis of an organism, (ed. Epstein, G. F. & Shakes, D. C.)., pp. 187–204. San Diego, CA: Academic Press.Google Scholar
Redman, C. A., Robertson, A., Fallon, P. G., Modha, J.Kusel, J. R., Doenhoff, M. J. & Martin, R. J. (1996). Praziquantel: an urgent and exciting challenge. Parasitology Today 12, 14–20.CrossRefGoogle ScholarPubMed
Rinehart, K. L., Holt, T. G., Fregeau, N. L., Keifer, P. A., Wilson, G. R., Perun, T. J. Jr,. Sakai, R., Thompson, A. G., Stroh, J. G., Shield, L. S., Seigler, D. S., Li, L. H., Martin, D. G., Grimmelikhuijzen, C. J. P. & Gade, G. (1990). Bioactive compounds from aquatic and terrestrial sources. Journal of Natural Products 53, 771–92.CrossRefGoogle ScholarPubMed
Ring, C. S., Sun, E., McKerrow, J. H., Lee, G. K., Rosenthal, P. J., Kuntz, I. D. & Cohen, F. E. (1993). Structure-based inhibitor design by using protein models for the development of antiparasitic agents. Proceedings of the National Academy of Sciences, USA 90, 3583–7.CrossRefGoogle ScholarPubMed
Rohrer, S. P., Birzin, E. T., Eary, C. H., Schaeffer, J. M. & Shoop, W. L. (1994). Ivermectin binding sites in sensitive and resistant Haemonchus contortus. Journal of Parasitology 80, 493–7.CrossRefGoogle ScholarPubMed
Rohrer, S. P., Evans, W. D. & Bergstrom, A. (1990). A membrane associated glutamate binding protein from Caenorhabditis elegans and Haemonchus contortus. Comparative Biochemistry and Physiology 95C, 223–8.Google ScholarPubMed
Roques, B. P., Noble, F., Crine, P. & Fournie-Zaluski, M. C. (1995). Inhibitors of neprilysin: design, pharmacological and clinical applications. Methods in Enzymology 248, 263–83.CrossRefGoogle ScholarPubMed
Rose, C., Vargas, F., Facchinetti, P., Bourgeat, P., Bambal, R. B., Bishop, P. B., Chan, S. M. T., Moore, A. N. J., Ganellin, C. R. & Schwartz, J.-C. (1996). Characterization and inhibition of a cholecystokinininactivating serine peptidase. Nature 380, 403–9.CrossRefGoogle ScholarPubMed
Ruben, L. & Rasmussen, H. (1981). Phenothiazines and related compounds disrupt mitochondrial energy production by a calmodulin-independent reaction. Biochimica et Biophysica Acta 637, 415–22.CrossRefGoogle ScholarPubMed
Sajid, M. & Isaac, R. E. (1994). Metabolism of AF1 (LysX-Asn-Glu-Phe-Ile-Arg-Phe-NH2) in the nematode Ascaris suum. Biochemical Society Transactions 22, 293S.CrossRefGoogle ScholarPubMed
Sajid, M. & Isaac, R. E. (1995). Identification and properties of a neuropeptide-degrading endopeptidase (neprilysin) of Ascaris suum muscle. Parasitology 111, 599–608.CrossRefGoogle ScholarPubMed
Sakube, Y., Ando, H. & Kagawa, H. (1993). Cloning and mapping of a ryanodine receptor homolog gene of Caenorhabditis elegans. Annals of the New York Academy of Sciences 707, 540–5.CrossRefGoogle ScholarPubMed
Sangster, N. C., Davis, C. W. & Collins, G. H. (1991). Effects of cholinergic drugs on longitudinal contraction in levamisole-susceptible and -resistant Haemonchus contortus. International Journal for Parasitology 21, 689–95.CrossRefGoogle ScholarPubMed
Sasaki, T., Takagi, M.Yaguchi, T., Miyadoh, S., Okada, T. & Koyama, M. (1992). A new anthelmintic cyclodepsipeptide, PF1022A. Journal of Antibiotics 45, 692–7.CrossRefGoogle ScholarPubMed
Schaeffer, J. M. & Bergstrom, A. R. (1988). Identification of gamma-aminobutyric acid and its binding sites in Caenorhabditis elegans. Life Sciences 43, 1701–6.CrossRefGoogle ScholarPubMed
Schaeffer, J. M., Bergstrom, A. R., Frazier, E. G. & Underwood, D. (1994). Nematocidal activity of MK-801 analogs and related drugs. Structure-activity relationships. Biochemical Pharmacology 48, 411–8.CrossRefGoogle ScholarPubMed
Schaeffer, J. M.,Bergstrom, A. R. & Turner, M. J. (1989). MK-801 is a potent nematocidal agent. Characterization of MK-801 binding sites in Caenorhabditis elegans. Biochemical Journal 260, 923–6.CrossRefGoogle ScholarPubMed
Schaeffer, J. M., Blizzard, T. A., Ondeyka, J., Goegelman, R., Sinclair, P. J. & Mrozik, H. (1992). [3H]Paraherquamide binding to Caenorhabditis elegans. Biochemical Pharmacology 43, 679–84.CrossRefGoogle ScholarPubMed
Schaeffer, J. M. & Donatelli, M. R. (1990). Characterization of a high-affinity membraneassociated ornithine decarboxylase from the free-living nematode Caenorhabditis elegans. Biochemical Journal 270, 599–604.CrossRefGoogle ScholarPubMed
Schaeffer, J. M. & Haines, H. W. (1989). Avermectin binding in Caenorhabditis elegans: a two-state model for the avermectin binding site. Biochemical Pharmacology 38, 2329–38.CrossRefGoogle ScholarPubMed
Schaeffer, J. M., Ruiz-Sanchez, J., Shih, T. L. & Mrozik, H. (1989). Argiopine differentiates between vertebrate and invertebrate glutamate binding sites. Pesticide Biochemistry and Physiology 35, 26–32.CrossRefGoogle Scholar
Schaeffer, J. M., White, T., Bergstrom, A. R., Wilson, K. E. & Turner, M. J. (1990). Identification of glutamate binding sites in Caenorhabditis elegans. Pesticide Biochemistry and Physiology 36, 220–8.CrossRefGoogle Scholar
Schafer, W. R. & Kenyon, C. J. (1995). A calcium channel homologue required for adaptation to dopamine and serotonin in Caenorhabditis elegans. Nature 375, 73–8.CrossRefGoogle ScholarPubMed
Scheuer, P. J. (1994). From the rainforest to the reef: searching for bioactive natural products in the mid-Pacific. Medicinal Research Reviews 14, 487–503.CrossRefGoogle Scholar
Schroeder, K. S. & Neagle, B. D. (1996). FLIPR - a new instrument for accurate, high throughput optical screening. Journal of Biomolecular Screening 2, 75–80.CrossRefGoogle Scholar
Segalat, L., Elkes, D. A. & Kaplan, J. M. (1995). Modulation of serotonin-controlled behaviors by Go in Caenorhabditis elegans. Science 267, 1648–51.CrossRefGoogle ScholarPubMed
Sengupta, P., Chou, J. H. & Bargmann, C. I. (1996). odr-10 encodes a seven transmembrane domain olfactory receptor required for responses to the odorant diacetyl. Cell 84, 899–909.CrossRefGoogle Scholar
Shoichet, B. K., Stroud, R. M., Santi, D. V., Kuntz, I. D. & Perry, K. M. (1993). Structure-based discovery of inhibitors of thymidylate synthase. Science 259, 1445–50.CrossRefGoogle ScholarPubMed
Shoop, W. L., Eary, C. H., Michael, B. F., Haines, H. W. & Seward, R. L. (1991). Anthelmintic activity of paraherquamide in dogs. Veterinary Parasitology 40, 339–41.CrossRefGoogle ScholarPubMed
Shoop, W. L., Egerton, J. R., Eary, C. H., & Suhayda, D. (1990). Anthelmintic activity of paraherquamide in sheep. Journal of Parasitology 76, 349–51.CrossRefGoogle ScholarPubMed
Sims, S. M., Ho, N. F. H., Magas, L. T., Geary, T. G., Barsuhn, C. L. & Thompson, D. P. (1994). Biophysical model of the transcuticular excretion of organic acids, cuticle pH and buffer capacity in gastrointestinal nematodes. Journal of Drug Targeting 2, 1–8.CrossRefGoogle ScholarPubMed
Sine, S. M. & Claudio, T. (1991). Stable expression of the mouse nicotinic acetylcholine receptor in mouse fibroblasts. Comparison of receptors in native and transfected cells. Journal of Biological Chemistry 266, 13679–89.CrossRefGoogle ScholarPubMed
Snider, R. M., Constantine, J. W., Lowe, J. A. III., Longo, K. P., Lebel, W. S., Woody, H. A., Drozda, S. E., Desai, M. C., Vinick, F. J., Spencer, R. W. & Hess, H-J. (1991). A potent nonpeptide antagonist of the substance P (NKj) receptor. Science 251, 435–9.CrossRefGoogle Scholar
Stretton, A. O. W. (1992). Chemical intracellular signalling mechanisms in the nervous system of the nematode Ascaris suum: potential sites of action of new generations of anthelmintic drugs. In Neurotox “91 (ed. Duce, I. R.), pp. 123–38. New York, NY: Elsevier Applied Science.Google Scholar
Stretton, A. O. W., Cowden, C., Sithigorngul, P. & Davis, R. E. (1991). Neuropeptides in the nematode Ascaris suum. Parasitology 102, S107–16.CrossRefGoogle ScholarPubMed
Strosberg, A. D. & Marullo, S. (1992). Functional expression of receptors in microorganisms. Trends in Pharmacological Sciences 13, 95–8.CrossRefGoogle ScholarPubMed
Sweetnam, P. M., Caldwell, L., Lancaster, J., Bauer, C. Jr., Mcmillan, B., Kinnier, W. J. & Price, C. H. (1993). The role of receptor binding in drug discovery. Journal of Natural Products 56, 441–5.CrossRefGoogle ScholarPubMed
Tembe, E. A., Holden-Dye, L., Smith, S. W. G., Jacques, P. A. M. & Walker, R. J. (1993). Pharmacological profile of the 5-hydroxytryptamine receptor of Fasciola hepatica body wall muscle. Parasitology 106, 67–73.CrossRefGoogle ScholarPubMed
Terada, M. (1992). Neuropharmacological mechanism of action of PF1022A, an antinematode anthelmintic with a structure of cyclic depsipeptide, on Angiostrongylus cantonensis and isolated frog rectus. Japanese Journal of Parasitology 41, 108–17.Google Scholar
Terada, M.Ishih, A., Tungtrongchitr, M., Sano, M. & Shomura, T. (1993). Effects of PF1022A on developing larvae of Angiostrongylus costaricensis in mice, with special reference to route, dose and formulation. Japanese Journal of Parasitology 42, 199–210.Google Scholar
Thompson, D. P., Chen, G.-Z., Sample, A. K., Semeyn, D. R. & Bennett, J. L. (1986). Calmodulin: biochemical, physiological and morphological effects on Schistosoma mansoni. American Journal of Physiology 251, R1051–8.Google ScholarPubMed
Thompson, D. P., Pax, R. A. & Bennett, J. L. (1982). Microelectrode studies of the tegument and subtegumental compartments of the male Schistosoma mansoni: an analysis of electrophysiological properties. Parasitology 85, 163–78.CrossRefGoogle ScholarPubMed
Tomoda, H. & Omura, S. (1990). New strategy for discovery of enzyme inhibitors: screening with intact mammalian cells or intact microorganisms having special functions. Journal of Antibiotics 43, 1207–22.CrossRefGoogle ScholarPubMed
Tornoe, C., Bai, D., Holden-Dye, L., Abramson, S. N. & Sattelle, D. B. (1995). Actions of neurotoxins (bungarotoxins, neosurugatoxin and lophotoxins) on insect and nematode nicotinic acetylcholine receptors. Toxicon 33, 411–24.CrossRefGoogle ScholarPubMed
Tsoi, C. J. & Khosla, C. (1995). Combinatorial biosynthesis of ‘unnatural’ natural products: the polyketide example. Chemistry & Biology 2, 35–62.Google ScholarPubMed
Umezawa, H. (1982). Low-molecular-weight enzyme inhibitors of microbial origin. Annual Review of Microbiology 36, 75–99.CrossRefGoogle ScholarPubMed
Valkanov, M. A. & Martin, R. J. (1995). A Cl channel in Ascaris suum selectively conducts dicarboxylic anion products of glucose fermentation and suggests a role in removal of waste organic anions. Journal of Membrane Biology 148, 41–9.CrossRefGoogle ScholarPubMed
Venuti, M. C. (1995). The role of recombinant DNA technology in medicinal chemistry and drug discovery. In Burger's Medicinal Chemistry and Drug Discovery, Vol. 1, (ed. Wolff, M. E.), pp. 661–96. New York, NY: John Wiley & Sons, Inc.Google Scholar
Von Itzstein, M., Wu, W.-Y., Kok, G. B., Pegg, M. S., Dyason, J. C., Jin, B., Phan, T. V., Smythe, M. L., White, H. F., Oliver, S. W., Colman, P. M., Varghese, J. N., Ryan, D. M., Woods, J. M., Bethell, R. C., Hotham, V. J., Cameron, J. M. & Penn, C. R. (1993). Rational design of potent sialidase-based inhibitors of influenza virus replication. Nature 363, 418–23.CrossRefGoogle ScholarPubMed
Waldmann, R.Champigny, G. & Lazdunski, M. (1995). Functional degenerin-containing chimeras identify residues essential for amiloride-sensitive Na+ channel function. Journal of Biological Chemistry 270, 11735–7.CrossRefGoogle ScholarPubMed
Walker, R. J. & Holden-Dye, L. (1991). Evolutionary aspects of transmitter molecules, their receptors and channels. Parasitology 102, S7–29.CrossRefGoogle ScholarPubMed
Wang, C. C. (1984). Parasite enzymes as potential targets for antiparasite chemotherapy. Journal of Medicinal Chemistry 27, 1–9.CrossRefGoogle Scholar
Wang, M. M. & Reed, R. R. (1993). Molecular cloning of the olfactory neuronal transcription factor Olf-1 by genetic selection in yeast. Nature 364, 121–6.CrossRefGoogle ScholarPubMed
Waterston, R. & Sulston, J. (1995). The genome of Caenorhabditis elegans. Proceedings of the National Academy of Sciences USA 92, 10836–40.CrossRefGoogle ScholarPubMed
Whittle, P. J. & Blundell, T. L. (1994). Protein structure-based drug design. Annual Review of Biophysics and Biomolecular Structure 23, 349–75.CrossRefGoogle ScholarPubMed
Williams, J. A., Shahkolahi, A. M., Abbassi, M. & Donahue, M. J. (1992). Identification of a novel 5-HTN (Nematoda) receptor from Ascaris suum muscle. Comparative Biochemistry and Physiology 101C, 469–74.Google ScholarPubMed
Williams, J. F., Ghalib, H. W., Mackenzie, C. D., El Khalifa, M. Y., Ayuya, J. M. & Kron, M. A. (1987). Cell adherence to microfilariae of Onchocerca volvulus: a comparative study. In Filariasis, Ciba Foundation Symposium 127 (ed. Evered, D. & Clark, C.), pp. 146–63. Chichester U.K.: John Wiley & Sons, Ltd.Google Scholar
Williams, M. (1991). Receptor binding in the drug discovery process. Medicinal Research Reviews 11, 147–84.CrossRefGoogle ScholarPubMed
Wilson, T. E., Fahrner, T. J., Johnson, M. & Milbrandt, J. (1991). Identification of DNA binding site for NGFI-B by genetic selection in yeast. Science 252, 1296–300.CrossRefGoogle ScholarPubMed
Wood, J. M., Cumin, F. & Maibaum, J. (1994). Pharmacology of renin inhibitors and their application to the treatment of hypertension. Pharmacology and Therapeutics 61, 325–44.CrossRefGoogle Scholar
Yamazaki, M., Okuyama, E., Kobayashi, M. & Inoue, H. (1981). The structure of paraherquamide, a toxic metabolite from Penicillium paraherquei. Tetrahedron Letters 22, 135–6.CrossRefGoogle Scholar
Yang, H.-Y. T. & Majane, E. A. (1990). Mammalian Phe-Met-Arg-Phe-NH2-like peptides: structure, biological activity and distribution. In Progress in Comparative Endocrinology (ed. Epple, A., Scanes, C. G. & Stetson, M. H.), pp. 86–91. New York, NY: Wiley-Liss, Inc.Google Scholar
Yarbrough, G. G., Taylor, D. P.., Rowlands, R. T., Crawford, M. S. & Lasure, L. L. (1993). Screening microbial metabolites for new drugs – theoretical and practical issues. Journal of Antibiotics 46, 535–44.CrossRefGoogle ScholarPubMed