Hostname: page-component-7c8c6479df-94d59 Total loading time: 0 Render date: 2024-03-28T12:08:13.625Z Has data issue: false hasContentIssue false

Progressing the global antimalarial portfolio: finding drugs which target multiple Plasmodium life stages

Published online by Cambridge University Press:  10 June 2013

PAUL W. SMITH
Affiliation:
Novartis Institute for Tropical Diseases, 10 Biopolis Road, #05-01 Chromos, Singapore138670
THIERRY T. DIAGANA
Affiliation:
Novartis Institute for Tropical Diseases, 10 Biopolis Road, #05-01 Chromos, Singapore138670
BRYAN K. S. YEUNG*
Affiliation:
Novartis Institute for Tropical Diseases, 10 Biopolis Road, #05-01 Chromos, Singapore138670
*
*Corresponding author. Novartis Institute for Tropical Diseases, 10 Biopolis Road, #05-01 Chromos, Singapore138670. Tel: (+65) 6722 2923. Fax: (+65) 6722 2918. E-mail: bryan.yeung@novartis.com

Summary

The number of novel antimalarial candidates entering preclinical development has seen an increase over the last several years. Most of these drug candidates were originally identified as hits coming from screening large chemical libraries specifically targeting the asexual blood stages of Plasmodium falciparum. Indeed, a large proportion of the current antimalarial arsenal has mainly targeted the asexual blood stage which is responsible for clinical symptoms of the disease. However, as part of the eradication agenda and to address resistance, any next-generation antimalarial should have additional activity on at least one other parasite life stage, i.e. gametocytocidal and/or tissue schizonticidal activity. We have applied this approach by screening compounds with intrinsic activity on asexual blood stages in assays against sexual and liver stages and identified two new antimalarial chemotypes with activity on multiple parasite life stages. This strategy can be expanded to identify other chemical classes of molecules with similar activity profiles for the next generation antimalarials. The following review summarizes the discovery of the spiroindolones and imidazolopiperazine classes of antimalarials developed by the NGBS consortium (Novartis Institute for Tropical Diseases, Genomic Institute of the Novartis Research Foundation, Biomedical Primate Research Center, and the Swiss Tropical and Public Health Institute) currently in clinical trials.

Type
Research Article
Copyright
Copyright © Cambridge University Press 2013 

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

REFERENCES

Anthony, M. P., Burrows, J. N., Duparc, S., Moehrle, J. J. and Wells, T. N. C. (2012). The global pipeline of new medicines for the control and elimination of malaria. Malaria Journal 11, 316340. doi:10.1186/1475-2875-11-316.Google Scholar
Chattopadhyay, R., Velmurugan, S., Chakiath, C., Andrews Donkor, L., Milhous, W., Barnwell, J. W., Collins, W. E. and Hoffman, S. L. (2010). Establishment of an in vitro assay for assessing the effects of drugs on the liver stages of Plasmodium vivax Malaria. PLoS ONE 5, e14275. doi:10.1371/journal.pone.0014275.Google Scholar
Cheeseman, I. H., Miller, B. A., Nair, S., Nkhoma, S., Tan, A., Tan, J. C., Al Saai, S., Phyo, A. P., Moo, C. L., Lwin, K. M., McGready, R., Ashley, E., Imwong, M., Stepniewska, K., Yi, P., Dondorp, A. M., Mayxay, M., Newton, P. N., White, N. J., Nosten, F., Ferdig, M. T. and Anderson, T. J. (2012). A major genome region underlying artemisinin resistance in malaria. Science 336, 7982.Google Scholar
Cogswell, F. B. (1992). The hypnozoite and relapse in primate malaria. Clinical Microbiology Reviews 5, 2635.Google Scholar
Delves, M., Plouffe, D., Scheurer, C., Meister, S., Wittlin, S., Winzeler, E. A., Sinden, R. E. and Leroy, D. (2012). The activities of current antimalarial drugs on the life cycle stages of Plasmodium: a comparative study with human and rodent parasites. PLoS Medicine 9, e1001169. doi:10.1371/journal.pmed.1001169.CrossRefGoogle ScholarPubMed
Dembele, L., Gego, A., Zeeman, A.-M., Franetich, J.-F., Silvie, O., Rametti, A., Le Grand, R., Dereuddre-Bosquet, N., Sauerwein, R., van Gemert, G.-J., Vaillant, J.-C., Thomas, A. W., Snounou, G., Kocken, C. H. M. and Mazier, D. (2011). Towards an in vitro model of Plasmodium hypnozoites suitable for drug discovery. PLoS ONE 6, e18162. doi:10.1371/journal.pone.0018162.CrossRefGoogle Scholar
Derbyshire, E. R., Prudencio, M., Mota, M. M. and Clardy, J. (2012). Liver-stage malaria parasites vulnerable to diverse chemical scaffolds. Proceedings of the National Academy of Sciences, USA 109, 85118516. doi:10.1073/pnas.1118370109.CrossRefGoogle ScholarPubMed
Dondorp, A. M., Nosten, F., Yi, P., Das, D., Phyo, A. P., Tarning, J., Lwin, K. M., Ariey, F., Hanpithakpong, W., Lee, S. J., Ringwald, P., Silamut, K., Imwong, M., Chotivanich, K., Lim, P., Herdman, T., An, S. S., Yeung, S., Singhasivanon, P., Day, N. P. J., Lindegardh, N., Socheat, D. and White, N. J. (2009). Artemisinin resistance in Plasmodium falciparum malaria. New England Journal of Medicine 36, 455467.Google Scholar
Dubin, A. E., Nasser, N., Rohrbacher, J., Hermans, A. N., Marrannes, R., Grantham, C., Van Rossem, K., Cik, M., Chaplan, S. R., Gallacher, D., Xu, J., Guia, A., Byrne, N. G. and Mathes, C. (2005). Identifying modulators of hERG channel activity using the PatchXpress planar patch clamp. Journal of Biomolecular Screening 10, 168181.Google Scholar
Grigoryan, N. P., Pogosyan, S. A. and Paronikyan, R. G. (2005). Synthesis and antispasmodic activity of spiro[β-carbolineindolones] and spiro[indoleindolo[2,3-c]azepinones]. Armenian Chemical Journal 58, 101104.Google Scholar
Guiguemde, W. A., Shelat, A. A., Garcia-Bustos, J. F., Diagana, T. T., Gamo, F.-J. and Guy, R. K. (2012). Global phenotypic screening for antimalarials. Chemistry and Biology 19, 116129. doi:10.1016/j.chembiol.2012.01.004.CrossRefGoogle ScholarPubMed
Huber, W. and Koella, J. A. (1993). Comparison of three methods of estimating EC50 in studies of drug resistance of malaria parasites. Acta Tropica 55, 257261.Google Scholar
Jonikas, M. C., Collins, S. R., Denic, V., Oh, E., Quan, E. M., Schmid, V., Weibezahn, J., Schwappach, B., Walter, P., Weissman, J. S. and Schuldiner, M. (2009). Comprehensive characterization of genes required for protein folding in the endoplasmic reticulum. Science 323, 16931697. doi:10.1126/science.1167983Google Scholar
Krishna, S., Woodrow, C., Webb, R., Penny, J., Takeyasu, K., Kimura, M. and East, J. M. (2001). Expression and functional characterization of a Plasmodium falciparum Ca2+-ATPase (PfATP4) belonging to a subclass unique to apicomplexan organisms. Journal of Biological Chemistry 276, 1078210787.CrossRefGoogle ScholarPubMed
Kühlbrandt, W. (2004) Nature Reviews. Biology, structure, and mechanism of P-type ATPases. Molecular and Cellular Biology 5, 282295.Google ScholarPubMed
Lau, Y. Y., Krishna, G., Yumibe, N. P., Grotz, D. E., Sapidou, E., Norton, L., Chu, I., Chen, C., Soares, A. D. and Lin, C. C. (2002). The use of in vitro metabolic stability for rapid selection of compounds in early discovery based on their expected hepatic extraction ratios. Pharmaceutical Research 19, 16061610.Google Scholar
Lelievre, J., Almela, M. J., Lozano, S., Miguel, C., Franco, V., Leroy, D. and Herreros, E. (2012). Activity of clinically relevant antimalarial drugs on Plasmodium falciparum mature gametocytes in an ATP bioluminescence ‘transmission blocking’ assay. PLoS ONE 7, e35019. doi:10.1371/journal.pone.0035019.Google Scholar
Liu, B., Chang, J., Gordon, W. P., Isbell, J., Zhou, Y. and Tuntland, T. (2007). Snapshot PK: a rapid rodent in vivo preclinical screening approach. Drug Discovery Today 13, 360367. doi:10.1016/j.drudis.2007.10.014.Google Scholar
Maeda, I., Kohara, Y., Yamamoto, M. and Sugimoto, A. (2001). Large-scale analysis of gene function in Caenorhabditis elegans by high-throughput RNAi. Current Biology 11, 171176.Google Scholar
Malleret, B., Claser, C., Ong, A. S., Suwanarusk, R., Sriprawat, K., Howland, S. W., Russell, B., Nosten, F. and Renia, L. (2011). A rapid and robust tri-color flow cytometry assay for monitoring malaria parasite development. Scientific Reports 1, 118128. doi:10.1038/srep00118.Google Scholar
Mathes, C. (2006). QPatch: the past, present and future of automated patch clamp. Expert Opinions on Therapeutic Targets 10, 319327.Google Scholar
Maude, R. J., Pontavornpinyo, W., Saralamba, S., Aguas, R., Yeung, S., Dondorp, A. M., Day, N. P., White, N. J. and White, L. J. (2009). The last man standing is the most resistant: eliminating artemisinin-resistant malaria in Cambodia. Malaria Journal 8, 3137.Google Scholar
Meister, S., Plouffe, D. M., Kuhen, K. L., Bonamy, G. M. C., Wu, T., Barnes, S. W., Bopp, S. E., Borboa, R., Bright, A. T., Che, J., Cohen, S., Dharia, N. V., Gagaring, K., Gettayacamin, M., Gordon, P., Groessl, T., Kato, N., Lee, M. C. S., McNamara, C. W., Fidock, D. A., Nagle, A., Nam, T. G., Richmond, W., Roland, J., Rottmann, M., Zhou, B., Froissard, P., Glynne, R. J., Mazier, D., Sattabongkot, J., Schultz, P. G., Tuntland, T., Walker, J. R., Zhou, Y., Chatterjee, A., Diagana, T. T. and Winzeler, E. A. (2011). Imaging of Plasmodium liver stages to drive next-generation antimalarial drug discovery. Science 334, 13721377. doi:10.1126/science.1211936.Google Scholar
Nam, T., McNamara, C. W., Bopp, S., Dharia, N. V., Meister, S., Bonamy, G. M. C., Plouffe, D. M., Kato, N., McCormack, S., Bursulaya, B., Ke, H., Vaidya, A. B., Schultz, P. G. and Winzeler, E. A. (2011). A chemical genomic analysis of decoquinate, a Plasmodium falciparum cytochrome b inhibitor. ACS Chemical Biology 6, 12141222.Google Scholar
Noedl, H., Se, Y., Schaecher, K., Smith, B. L., Socheat, D. and Fukuda, M. M. (2008). Evidence of artemisinin-resistant malaria in western Cambodia. New England Journal of Medicine 359, 26192620.CrossRefGoogle ScholarPubMed
Obach, R. S., Baxter, J. G., Liston, T. E., Silber, B. M., Jones, B. C., MacIntyre, F., Rance, D. J. and Wastall, P. (1997). The prediction of human pharmacokinetic parameters from preclinical and in vitro metabolism data. Journal of Pharmacology and Experimental Therapeutics 283, 4658.Google Scholar
Phyo, A. P., Nkhoma, S., Stepniewska, K., Ashley, E. A., Nair, S., McGready, R., ler Moo, C., Al-Saai, S., Dondorp, A. M., Lwin, K. M., Singhasivanon, P., Day, N. P., White, N. J., Anderson, T. J. and Nosten, F. (2012). Emergence of artemisinin-resistant malaria on the western border of Thailand: a longitudinal study. Lancet 379, 19601966.Google Scholar
Plouffe, D., Brinker, A., McNamara, C., Henson, K., Kato, N., Kuhen, K., Nagle, A., Adrian, F., Matzen, J. T., Anderson, P., Nam, T. G., Gray, N. S., Chatterjee, A., Janes, J., Yan, S. F., Trager, R., Caldwell, J. S., Schultz, P. G., Zhou, Y. and Winzeler, E. A. (2008). In silico activity profiling reveals the mechanism of action of antimalarials discovered in a high-throughput screen. Proceedings of the National Academy of Sciences, USA 105, 90599064.Google Scholar
Price, R. N., Tjitra, E., Guerra, C. A., Yeung, S., White, N. J. and Anstey, N. M. (2007). Vivax malaria: neglected and not benign. American Journal of Tropical Medicine and Hygiene 77, 7987.Google Scholar
Rottmann, M., McNamara, C., Yeung, B. K. S., Lee, M. C. S., Zou, B., Russell, B., Seitz, P., Plouffe, D. M., Dharia, N. V., Tan, J., Cohen, S. B., Spencer, K. R., González-Páez, G. E., Lakshminarayana, S. B., Goh, A., Suwanarusk, R., Jegla, T., Schmitt, E. K., Beck, H.-P., Brun, R., Nosten, F., Renia, L., Dartois, V., Keller, T. H., Fidock, D. A., Winzeler, E. A. and Diagana, T. T. (2010). Spiroindolones, a potent compound class for the treatment of malaria. Science 329, 11751180.Google Scholar
Russell, B., Suwanarusk, R., Malleret, B., Costa, F. T. M., Snounou, G., Baird, J. K., Nosten, F. and Rénia, L. (2012). Human ex vivo studies on asexual Plasmodium vivax: the best way forward. International Journal for Parasitology 42, 10631070.Google Scholar
Spillman, N. J., Allen, R. J., McNamara, C. W., Yeung, B. K. S., Winzeler, E. A., Diagana, T. T. and Kirk, K. (2013). Na+ regulation in the malaria parasite Plasmodium falciparum involves the cation ATPase PfATP4 and is a target of the spiroindolone antimalarials. Cell Host and Microbe 13, 227237. doi: 10.1016/j.chom.2012.12.006.Google Scholar
Wells, T. N. C. (2011). Natural products as starting points for future anti-malarial therapies: going back to our roots? Malaria Journal 10, S3.Google Scholar
Wu, T., Nagle, A., Kuhen, K., Gagaring, K., Borboa, R., Francek, C., Chen, Z., Plouffe, D., Goh, A., Lakshminarayana, S. B., Wu, J., Ang, H. Q., Zeng, P., Kang, M. L., Tan, W., Tan, M., Ye, N., Lin, X., Caldwell, C., Ek, J., Skolnik, S., Liu, F., Wang, J., Chang, J., Li, C., Hollenbeck, T., Tuntland, T., Isbell, J., Fischli, C., Brun, R., Rottmann, M., Dartois, V., Keller, T., Diagana, T., Winzeler, E., Glynne, R., Tully, D. C. and Chatterjee, A. K. (2011). Imidazolopiperazines: hit to lead optimization of new antimalarial agents. Journal of Medicinal Chemistry 54, 51165130.Google Scholar
van der Kolk, M., De Vlas, S. J., Saul, A., van de Vegte-Bolmer, M., Eling, W. M. and Sauerwein, R. W. (2005). Evaluation of the standard membrane feeding assay (SMFA) for the determination of malaria transmission reducing activity using empirical data. Parasitology 130, 1322.Google Scholar
van Pelt-Koops, J. C., Pett, H. E., Graumans, W., van der Vegte-Bolmer, M., van Gemert, G. J., Rottmann, M., Yeung, B. K. S., Diagana, T. T. and Sauerwein, R. W. (2012). The spiroindolone drug candidate NITD609 potently inhibits gametocytogenesis and blocks Plasmodium falciparum transmission to anopheles mosquito vector. Antimicrobial Agents and Chemotherapy 56, 35443548. doi: 10.1128/AAC.06377-11.Google Scholar
Winzeler, E. A., Shoemaker, D. D., Astromoff, A., Liang, H., Anderson, K., Andre, B., Bangham, R., Benito, R., Boeke, J. D., Bussey, H., Chu, A. M., Connelly, C., Davis, K., Dietrich, F., Dow, S. W., El Bakkoury, M., Foury, F., Friend, S. H., Gentalen, E., Giaever, G., Hegemann, J. H., Jones, T., Laub, M., Liao, H., Liebundguth, N., Lockhart, D. J., Lucau-Danila, A., Lussier, M., M'Rabet, N., Menard, P., Mittmann, M., Pai, C., Rebischung, C., Revuelta, J. L., Riles, L., Roberts, C. J., Ross-MacDonald, P., Scherens, B., Snyder, M., Sookhai-Mahadeo, S., Storms, R. K., Veronneau, S., Voet, M., Volckaert, G., Ward, T. R., Wysocki, R., Yen, G. S., Yu, K., Zimmermann, K., Philippsen, P., Johnston, M. and Davis, R. W. (1999). Functional characterization of the S. cerevisiae genome by gene deletion and parallel analysis. Science 285, 901906. doi:10.1126/science.285.5429.901.Google Scholar
Yatime, L., Buch-Pedersen, M. J., Musgaard, M., Morth, J. P., Lund Winther, A. M., Pedersen, B. P., Olesen, C., Andersen, J. P., Vilsen, B., Schiøtt, B., Palmgren, M. G., Møller, J. V., Nissen, P. and Fedosova, N. (2009). P-type ATPases as drug targets: tools for medicine and science. Biochimica et Biophysica Acta 1787, 207220.CrossRefGoogle ScholarPubMed
Yeung, B. K. S., Zou, B., Rottmann, M., Lakshminarayana, S. B., Ang, S. H., Leong, S. H., Tan, J., Wong, J., Keller-Maerki, S., Fischli, C., Goh, A., Schmitt, E. K., Krastel, P., Francotte, E., Kuhen, K., Plouffe, D., Henson, K., Wagner, T., Winzeler, E. A., Petersen, F., Brun, R., Dartois, V., Diagana, T. T. and Keller, T. H. (2010). Spirotetrahydro β-carbolines (spiroindolones): A new class of potent and orally efficacious compounds for the treatment of malaria. Journal of Medicinal Chemistry 53, 51555164.CrossRefGoogle ScholarPubMed
Zheng, W., Spencer, R. H. and Kiss, L. (2004). High throughput assay technologies for ion channel drug discovery. Assays and Drug Development Technologies 2, 543552.Google Scholar