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Screening and synthesis: high throughput technologies applied to parasitology

Published online by Cambridge University Press:  12 May 2005

R. E. MORGAN  and
N. J. WESTWOOD
R. E. MORGAN
Affiliation:
School of Chemistry and the Centre for Biomolecular Sciences, University of St Andrews, North Haugh, St Andrews, Fife, KY16 9ST, UK
N. J. WESTWOOD
Affiliation:
School of Chemistry and the Centre for Biomolecular Sciences, University of St Andrews, North Haugh, St Andrews, Fife, KY16 9ST, UK
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Abstract

High throughput technologies continue to develop in response to the challenges set by the genome projects. This article discusses how the techniques of both high throughput screening (HTS) and synthesis can influence research in parasitology. Examples of the use of targeted and phenotype-based HTS using unbiased compound collections are provided. The important issue of identifying the protein target(s) of bioactive compounds is discussed from the synthetic chemist's perspective. This article concludes by reviewing recent examples of successful target identification studies in parasitology.

Keywords

High throughput screeningautomated synthesisaffinity chromatographyprotozoanreviewtechnologytarget identificationchemical geneticscompound collectionphenotypic assay
Type
Research Article
Information
Parasitology , Volume 128 , Issue S1 , October 2004 , pp. S71 - S79
Copyright
© 2004 Cambridge University Press

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References

REFERENCES

ASAI, T., TAKEUCHI, T., DIFFENDERFER, J. & SIBLEY, D. ( 2002). Identification of small-molecule inhibitors of nucleoside triphosphate hydrolase in Toxoplasma gondii. Antimicrobial Agents and Chemotheraphy 46, 2393–2399.CrossRefGoogle Scholar
ARONOV, A. M., MUNAGALA, N. R., ORTIZ DE MONTELLANO, P. R., KUNTZ, I. D. & WANG, C. C. ( 2000). Rational design of selective submicromolar inhibitors of Tritichomonas foetus hypoxanthine-guanine-xanthine phosphoribosyltransferase. Biochemistry 39, 4684–4691.CrossRefGoogle Scholar
BOND, C. S., ZHANG, Y., BERRIMEN, M., CUNNINGHAM, M. L., FAIRLAMB, A. H. & HUNTER, W. N. ( 1999). Crystal structure of Trypanosoma cruzi trypanothoine reductase in complex with trypanothione, and the structure-based discovery of new natural product inhibitors. Structure 7, 81–89.CrossRefGoogle Scholar
BURDINE, L. & KODADEK, T. ( 2004). Target identification in chemical genetics: the (often) missing link. Chemistry and Biology 11, 593–597.CrossRefGoogle Scholar
CAREY, K. L., WESTWOOD, N. J., MITCHISON, T. J. & WARD, G. E. ( 2004). A small-molecule approach to studying invasive mechanisms of Toxoplasma gondii. Proceedings of the National Academy of Sciences, USA 101, 7433–7438.CrossRefGoogle Scholar
CHOWDHURY, S. F., DI LUCREZIA, R., GUERRERO, R. H., BRUN, R., GOODMAN, J., RUIZ-PEREZ, L. M., PACANOWSKA, D. G. & GILBERT, I. H. ( 2001). Novel inhibitors of Leishmanial dihydrofolate reductase. Bioorganic and Medicinal Chemistry Letters 11, 977–980.CrossRefGoogle Scholar
DONALD, R. G. K., ALLOCCO, J., SINGH, S. B., NARE, B., SALOWE, S. P., WILTSIE, J. & LIBERSTOR, P. A. ( 2002). Toxoplasma gondii cyclic GMP-dependent kinase: Chemotherapeutic targeting of an essential parasite protein kinase. Eukaryotic Cell 1, 317–328.CrossRefGoogle Scholar
DORMÁN, G. & PRESTWICH, G. D. ( 2000). Using photolabile ligands in drug discovery and development. Trends in Biotechnology 18, 64–77.CrossRefGoogle Scholar
FREYMANN, D. M., WENCK, M. A., ENGEL, J. C., FENG, J., FOCIA, P. J., EAKIN, A. E. & CRAIG III, S. P. ( 2000). Efficient identification of inhibitors targeting the closed active site conformation of the HPRT from Trypanosoma cruzi Chemistry and Biology 7, 957–968.Google Scholar
GRANT, K. M., DUNOIN, M. H., YARDLEY, V., SKALTSOUNIS, A.-L., MARKO, D., EISENBRAND, G., CROFT, S. L., MEIJER, L. & MOTTAM, J. C. ( 2004). Inhibitors of Leishmania mexicana CRK3 cyclin-dependent kinase chemical library screen and anitleishmanial activity. Antimicrobial Agents and Chemotherapy 48, 3033–3042.CrossRefGoogle Scholar
GRAVES, P. R., KWIEK, J. J., FADDEN, P., RAY, R., HARDEMAN, K., COLEY, A. M., FOLEY, M. & HAYSTEAD, T. A. J. ( 2002). Discovery of novel targets of quinoline drugs in the human purine binding proteome. Molecular Pharmacology 62, 1364–1373.CrossRefGoogle Scholar
GRAY, N. S. ( 2001). Combinatorial libraries and biological discovery. Current Opinion in Neurobiology 11, 608–614.CrossRefGoogle Scholar
GURNETT, A. M., LIBERATOR, P. A., DULSKI, P. M., SALOWE, S. P., DONALD, R. G. K., ANDERSON, J. W., WILTSIE, J., DIAZ, C. A., BLUM, P. S., MISURA, A. S., TAMAS, T., SARDANA, M. K., YUAN, J., BIFTU, T. & SCHMATZ, D. M. ( 2002). Purification and molecular characterization of cGMP-dependent protein kinase from apicomplexan parasites. A novel chemothreapeutic Target. Journal of Biological Chemistry 277, 15913–15922.CrossRefGoogle Scholar
HARMSE, L., VAN ZYL, R., GRAY, N., SCHULTZ, P., LECLERC, S., MEIJER, L., DOERIG, C. & HAVLIK, I. ( 2001). Structure-activity relationships and inhibitory effects of various purine derivatives on the in vitro growth of Plasmodium falciparum. Biochemical Pharmacology 62, 341–348.CrossRefGoogle Scholar
HIRD, N. W. ( 1999). Automated synthesis: new tools for the organic chemist. Drug Discovery Today 4, 265–274.CrossRefGoogle Scholar
HORVATH, D. ( 1997). A virtual screening approach applied to the search for trypanothoine reductase inhibitors. Journal of Medicinal Chemistry 40, 2412–2423.CrossRefGoogle Scholar
KING, R. W. ( 1999). Chemistry or biology: which comes first after the genome is sequenced? Chemistry and Biology 6, R327–R333.Google Scholar
KNOCKAERT, M., GRAY, N., DAMIENS, E., CHANG, Y.-T., GRELLIER, P., GRANT, K., FERGUSSON, D., MATTRAM, J., SOETE, M., DUBREMETZ, J.-F., LE ROCH, K., DOERIG, C., SCHULTZ, P. G. & MEIJER, L. ( 2000). Intracellular targets of cyclin-dependent kinase inhibitors: identification by affinity chromatography using immobilised inhibitors. Chemistry and Biology 7, 411–422.CrossRefGoogle Scholar
KOEHLER, A. N., SHAMJI, A. F. & SCHREIBER, S. L. ( 2003). Discovery of an inhibitor of a transcription factor using small molecule microarrays and diversity-oriented synthesis. Journal of the American Chemical Society 125, 8420–8421.CrossRefGoogle Scholar
LEY, S. V. & BAXENDALE, I. R. ( 2002). New tools and concepts for modern organic synthesis. Nature Reviews Drug Discovery 1, 573–586.CrossRefGoogle Scholar
LIN, H., ABIDA, W. M., SAUER, R. T. & CORNISH, V. W. ( 2000). Dexamethasone-Methotrexate: an efficient chemical inducer of protein dimerization in vivo. Journal of the American Chemical Society 122, 4247–4248.CrossRefGoogle Scholar
LOKEY, R. S. ( 2003). Forward chemical genetics: progress and obstacles on the path to new pharmacopoeia. Current Opinion in Chemical Biology 7, 91–96.CrossRefGoogle Scholar
MAYER, T. U., KAPOOR, T. M., HAGGARTY, S. J., KING, R. W., SCHREIBER, S. L. & MITCHISON, T. J. ( 1999). Small molecule inhibitor of mitotic spindle bipolarity identified in a phenotype-based screen. Science 286, 971–974.CrossRefGoogle Scholar
NARE, B., ALLOCCO, J. J., LIBERATOR, P. A. & DONALD, R. G. K. ( 2002). Evaluation of a cyclic GMP-dependent protein kinase inhibitor in treatment of murine toxoplasmosis: gamma interferon is required for efficacy. Antimicrobial Agents and Chemotherapy 46, 300–307.CrossRefGoogle Scholar
PATTERSON, S., LORENZ, C., SLAWIN, A. M. Z. & WESTWOOD, N. J. ( 2004). Rapid access to a pentacyclic library core structure: a microwave assisted approach. QSAR and Combinatorial Science 23, 883–890.CrossRefGoogle Scholar
RASTELLI, G., PACCHIONI, S., SIRAWARAPON, R., PARENTI, M. D. & FERRARI, A. M. ( 2003). Docking and database screening reveal new classes of Plasmodium falciparum dihydrofolate reductase inhibitors. Journal of Medicinal Chemistry 46, 2834–2845.CrossRefGoogle Scholar
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, 3583–3587.CrossRefGoogle Scholar
SAMSON, I., KERREMANS, L., ROZENSKI, J., SAMYN, B., VAN BEEUMEN, J., VAN AERSCOT, A. & HERDEWIJN, P. ( 1995). Identification of a peptide inhibitor against glycosomal phosphoglycerate kinase of Trypanosoma brucei by a synthetic peptide library approach. Bioorganic and Medicinal Chemistry 3, 257–265.CrossRefGoogle Scholar
SCHWIKKARD, S. & VAN HEERDEN, F. R. ( 2002). Antimalarial activity of plant metabolites. Natural Products Reports 19, 675–692.CrossRefGoogle Scholar
SELZER, P. M., CHEN, X., CHAN, V. J., CHENG, M., KENYON, G. L., KUNTZ, I. D., SAKANARI, J. A., COHEN, F. E. & McKERROW, J. H. ( 1997). Leishmania major: Molecular modeling of cysteine proteases and prediction of new Nonpeptide Inhibitors. Experimental Parasitology 87, 212–221.CrossRefGoogle Scholar
SMITH, T. K., CROSSMAN, A., BRIMACOMBE, J. S. & FERGUSON, A. J. ( 2004). Chemical validation of GPI biosynthesis as a drug target against African sleeping sickness. The EMBO Journal 23, 4701–4708.CrossRefGoogle Scholar
SPENCER, D. M., WANDLESS, T. J., SCHREIBER, S. L. & CRABTREE, G. R. ( 1993). Controlling signal-transduction with synthetic ligands. Science 262, 1019–1024.CrossRefGoogle Scholar
TOYODA, T., BROBEY, R. K. B., SANO, G.-I., HORII, T., TOMIOKA, N. & ITAI, A. ( 1997). Lead discovery of inhibitors if the dihydrofolate reductase domain of Plasmodium falciparum dihydrofolate reductase-thymidylate synthase. Biochemical and Biophysical Research Communications 235, 515–519.CrossRefGoogle Scholar
VERKMAN, A. S. ( 2004). Drug discovery in academia. American Journal of Physiology and Cell Physiology 286, C465–C474.CrossRefGoogle Scholar
WARD, G. E., CAREY, K. L. & WESTWOOD, N. J. ( 2002). Using small molecules to study big questions in cellular microbiology. Cellular Microbiology 4, 471–482.CrossRefGoogle Scholar
WERBOVETZ, K. A. ( 2000). Target based drug discovery for Malaria, Leishmaniasis and Trypanosomiasis. Current Medicinal Chemistry 7, 835–860.Google Scholar
WIERSMA, H. I., GALUSKA, S. E., TOMLEY, F. M., SIBLEY, L. D., LIBERATOR, P. A. & DONALD, R. G. K. ( 2004). A role for coccidian cGMP-dependent protein kinase in motility and invasion. International Journal for Parasitology 34, 369–380.CrossRefGoogle Scholar
YARROW, J. C., PERLMAN, Z. E., WESTWOOD, N. J. & MITCHISON, T. J. ( 2004). A high throughput cell migration assay using scratch wound healing, a comparison of image-based readout methods. BMC Biotechnology 4, 1–9.Google Scholar
ZUCCOTTO, F., ZVELEBIL, M., BRUN, R., CHOWDHURY, S. F., DI LUCREZIA, R., RIUZ-PEREZ, L. M., PACANOWSKA, D. G. & GILBERT, I. H. ( 2001). Novel inhibitors of Trypanosoma cruzi dihydrofolate reductase. European Journal of Medicinal Chemistry 36, 395–405.CrossRefGoogle Scholar