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Screening strategies to identify new chemical diversity for drug development to treat kinetoplastid infections

Published online by Cambridge University Press:  28 August 2013

ROB DON  and
JEAN-ROBERT IOSET
ROB DON
Affiliation:
Drugs for Neglected Diseases initiative, 15 Chemin Louis-Dunant, 1202 Geneva, Switzerland
JEAN-ROBERT IOSET*
Affiliation:
Drugs for Neglected Diseases initiative, 15 Chemin Louis-Dunant, 1202 Geneva, Switzerland
*
*Corresponding author: Drugs for Neglected Diseases initiative, 15 Chemin Louis-Dunant, 1202 Geneva, Switzerland. Tel: +41 (0) 22 906 92 65. Fax: +41 (0) 22 906 92 31. E-mail: [email protected]
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Summary

The Drugs for Neglected Diseases initiative (DNDi) has defined and implemented an early discovery strategy over the last few years, in fitting with its virtual R&D business model. This strategy relies on a medium- to high-throughput phenotypic assay platform to expedite the screening of compound libraries accessed through its collaborations with partners from the pharmaceutical industry. We review the pragmatic approaches used to select compound libraries for screening against kinetoplastids, taking into account screening capacity. The advantages, limitations and current achievements in identifying new quality series for further development into preclinical candidates are critically discussed, together with attractive new approaches currently under investigation.

Keywords

High-throughputhigh-contentscreeningDNDilibrary selectionhuman African trypanosomiasisLeishmaniasisChagas' disease
Type
Research Article
Information
Parasitology , Volume 141 , Issue 1: Symposia of the British Society for Parasitology volume 49 Emerging paradigms in anti-infective drug design , January 2014 , pp. 140 - 146
Copyright
Copyright © Cambridge University Press 2013 

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References

REFERENCES

Bell, A. S., Bradley, J., Everett, J. R., Knight, M., Loesel, J., Mathias, J., McLoughlin, D., Mills, J., Sharp, R. E., Williams, C. and Wood, T. P. (2013). Plate-based diversity subset screening: an efficient paradigm for high throughput screening of a large screening file. Molecular Diversity 17, 319–335. doi: 10.1007/s11030-013-9438-x.Google Scholar
Castillo, E. A., Dea-Ayuela, M., Bolas-Fernandez, F., Rangel, M. E. and Gonzalez-Rosende, M. (2010). The kinetoplastid chemotherapy revisited: current drugs, recent advances and future perspectives. Current Medicinal Chemistry 17, 4027–4051.Google Scholar
Chawla, B. and Madhubala, R. (2010). Drug target in Leishmania. Journal of Parasitology Disease 34, 1–13.Google Scholar
Das, A., Dasgupta, A., Sengupta, T. and Majumder, H. K. (2004). Topoisomerases of kinetoplastid parasites as potential chemotherapeutic targets. Trends in Parasitology, 20, 381–387.Google Scholar
De Rycker, M., Hallyburton, I., Thomas, J., Campbell, L., Wyllie, S., Joshi, D., Cameron, S., Gilbert, I. H., Wyatt, P. G., Frearson, J. A., Fairlamb, A. H. and Gray, D. W. (2013). Comparison of a high-throughput high-content intracellular Leishmania donovani assay with an axenic amastigote assay. Antimicrobial Agents and Chemotherapy 57, 2913–2922. doi: 10.1128/AAC.02398-12.CrossRefGoogle ScholarPubMed
Feher, M. and Schmidt, J. M. (2003). Property distributions: differences between drugs, natural products, and molecules from combinatorial chemistry. Journal of Chemical Information and Modeling 43, 218–227.Google Scholar
Frearson, J. A., Brand, S., McElroy, S. P., Cleghorn, L. A., Smid, O., Stojanovski, L., Price, H. P., Guther, M. L., Torrie, L. S., Robinson, D. A., Hallyburton, I., Mpamhanga, C. P., Brannigan, J. A., Wilkinson, A. J., Hodgkinson, M., Hui, R., Qiu, W., Raimi, O. G., van Aalten, D. M., Brenk, R., Gilbert, I. H., Read, K. D., Fairlamb, A. H., Ferguson, M. A., Smith, D. F. and Wyatt, P. G. (2010). N-myristoyltransferase inhibitors as new leads to treat sleeping sickness. Nature 464, 728–732. doi: 10.1038/nature08893.Google Scholar
Frearson, J. A., Wyatt, P. G., Gilbert, I. H. and Fairlamb, A. H. (2007). Target assessment for antiparasitic drug discovery. Trends in Parasitology 23, 589–595.Google Scholar
Gamo, F. J., Sanz, L. M., Vidal, J., de Cozar, C., Alvarez, E., Lavandera, J. L., Vanderwall, D. E., Green, D. V., Kumar, V., Hasan, S., Brown, J. R., Peishoff, C. E., Cardon, L. R. and Garcia-Bustos, J. F. (2010). Thousands of chemical starting points for antimalarial lead identification. Nature 465, 305–310. doi: 10.1038/nature09107.Google Scholar
Ioset, J.-R. and Chang, S. (2011). Drugs for neglected diseases initiative model of drug development for neglected diseases: current status and future challenges. Future Medicinal Chemistry 1, 1361–1371. doi: 10.4155/fmc.11.102.Google Scholar
Jamal, S. and Periwal, V. (2013). Open source drug discovery consortium, Scaria V. Predictive modeling of anti-malarial molecules inhibiting apicoplast formation. BMC Bioinformatics 15, 55–62. 14:55. doi: 10.1186/1471-2105-14-55.CrossRefGoogle Scholar
Keller, T. H., Shi, P. Y. and Wang, Q. Y. (2011). Anti-infectives: can cellular screening deliver? Current Opinion in Chemical Biology 15, 529–533. doi: 10.1016/j.cbpa.2011.06.007.Google Scholar
Kima, P. E. (2007). The amastigote forms of Leishmania are experts at exploiting host cell processes to establish infection and persist. International Journal for Parasitology 37, 1087–1096.Google Scholar
Kogej, T., Blomberg, N., Greasley, P. J., Mundt, S., Vainio, M. J., Schamberger, J., Schmidt, G. and Hüser, J. (2013). Big pharma screening collections: more of the same or unique libraries? The AstraZeneca-Bayer Pharma AG case. Drug Discovery Today http://dx.doi.org/10.1016/j.drudis.2012.10.011.Google Scholar
Lang, T., Hellio, R., Kaye, P. M. and Antoine, J. C. (1994). Leishmania donovani-infected macrophages: characterization of the parasitophorous vacuole and potential role of this organelle in antigen presentation. Journal of Cell Science 107, 2137–2150.Google Scholar
McKerrow, J. H., Rosenthal, P. J., Swenerton, R. and Doyle, P. (2008). Development of protease inhibitors for protozoan infections. Current Opinion in Infectious Diseases 21, 668–672. doi: 10.1097/QCO.0b013e328315cca9.Google Scholar
Payne, D. J., Gwynn, M. N., Holmes, D. J., and Pompliano, D. L. (2007). Drugs for bad bugs: confronting the challenges of antibacterial discovery. Nature Reviews Drug Discovery 6, 29–40.Google Scholar
Periwal, V. and Kishtapuram, S. (2012). Open Source Drug Discovery Consortium, Scaria V. Computational models for in-vitro anti-tubercular activity of molecules based on high-throughput chemical biology screening datasets. BMC Pharmacology 31, 1–7. 12:1. doi: 10.1186/1471-2210-12-1.CrossRefGoogle Scholar
Pescher, P., Blisnick, T., Bastin, P. and Spath, G. F. (2011). Quantitative proteome profiling informs on phenotypic traits that adapt Leishmania donovani for axenic and intracellular proliferation. Cell Microbiology 13, 978–991. doi: 10.1111/j.1462-5822.2011.01593.x.Google Scholar
Renslo, A. R. and McKerrow, J. H. (2006). Drug discovery and development for neglected parasitic diseases. Nature Chemical Biology 2, 701–710.CrossRefGoogle ScholarPubMed
Sams-Dodd, F. (2005). Target-based drug discovery: is something wrong? Drug Discovery Today 10, 139–147.Google Scholar
Siqueira-Neto, J. L., Moon, S., Jang, J., Yang, G., Lee, C., Moon, H. K., Chatelain, E., Genovesio, A., Cechetto, J. and Freitas-Junior, L. H. (2012). An image-based high-content screening assay for compounds targeting intracellular Leishmania donovani amastigotes in human macrophages. PLoS Neglected Tropical Diseases 6, e1671. doi: 10.1371/journal.pntd.0001671.CrossRefGoogle ScholarPubMed
Sykes, M. L. and Avery, V. M. (2009). Development of an Alamar Blue viability assay in 384-well format for high throughput whole cell screening of Trypanosoma brucei brucei bloodstream form strain 427. American Journal of Tropical Medicine and Hygiene 81, 665–674. doi: 10.4269/ajtmh.2009.09-0015.Google Scholar
Wyatt, P. G., Gilbert, I. H., Read, K. D. and Fairlamb, A. H. (2011). Target validation: linking target and chemical properties to desired product profile. Current Topics in Medicinal Chemistry 11, 1275–1283.CrossRefGoogle ScholarPubMed