Skip to main content Accessibility help
×
Home
Hostname: page-component-55597f9d44-l69ms Total loading time: 0.525 Render date: 2022-08-08T05:13:04.589Z Has data issue: true Feature Flags: { "shouldUseShareProductTool": true, "shouldUseHypothesis": true, "isUnsiloEnabled": true, "useRatesEcommerce": false, "useNewApi": true } hasContentIssue true

Article contents

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
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: jrioset@dndi.org

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.

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

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, 319335. doi: 10.1007/s11030-013-9438-x.CrossRefGoogle ScholarPubMed
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, 40274051.CrossRefGoogle ScholarPubMed
Chawla, B. and Madhubala, R. (2010). Drug target in Leishmania. Journal of Parasitology Disease 34, 113.CrossRefGoogle ScholarPubMed
Das, A., Dasgupta, A., Sengupta, T. and Majumder, H. K. (2004). Topoisomerases of kinetoplastid parasites as potential chemotherapeutic targets. Trends in Parasitology, 20, 381387.CrossRefGoogle ScholarPubMed
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, 29132922. 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, 218227.Google ScholarPubMed
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, 728732. doi: 10.1038/nature08893.CrossRefGoogle ScholarPubMed
Frearson, J. A., Wyatt, P. G., Gilbert, I. H. and Fairlamb, A. H. (2007). Target assessment for antiparasitic drug discovery. Trends in Parasitology 23, 589595.CrossRefGoogle ScholarPubMed
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, 305310. doi: 10.1038/nature09107.CrossRefGoogle ScholarPubMed
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, 13611371. doi: 10.4155/fmc.11.102.CrossRefGoogle 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, 5562. 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, 529533. doi: 10.1016/j.cbpa.2011.06.007.CrossRefGoogle ScholarPubMed
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, 10871096.CrossRefGoogle 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.CrossRefGoogle ScholarPubMed
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, 21372150.Google ScholarPubMed
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, 668672. doi: 10.1097/QCO.0b013e328315cca9.CrossRefGoogle ScholarPubMed
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, 2940.CrossRefGoogle ScholarPubMed
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, 17. 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, 978991. doi: 10.1111/j.1462-5822.2011.01593.x.CrossRefGoogle ScholarPubMed
Renslo, A. R. and McKerrow, J. H. (2006). Drug discovery and development for neglected parasitic diseases. Nature Chemical Biology 2, 701710.CrossRefGoogle ScholarPubMed
Sams-Dodd, F. (2005). Target-based drug discovery: is something wrong? Drug Discovery Today 10, 139147.CrossRefGoogle ScholarPubMed
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, 665674. doi: 10.4269/ajtmh.2009.09-0015.CrossRefGoogle ScholarPubMed
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, 12751283.CrossRefGoogle ScholarPubMed
100
Cited by

Save article to Kindle

To save this article to your Kindle, first ensure coreplatform@cambridge.org is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about saving to your Kindle.

Note you can select to save to either the @free.kindle.com or @kindle.com variations. ‘@free.kindle.com’ emails are free but can only be saved to your device when it is connected to wi-fi. ‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

Find out more about the Kindle Personal Document Service.

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

Save article to Dropbox

To save this article to your Dropbox account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you used this feature, you will be asked to authorise Cambridge Core to connect with your Dropbox account. Find out more about saving content to Dropbox.

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

Save article to Google Drive

To save this article to your Google Drive account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you used this feature, you will be asked to authorise Cambridge Core to connect with your Google Drive account. Find out more about saving content to Google Drive.

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

Reply to: Submit a response

Please enter your response.

Your details

Please enter a valid email address.

Conflicting interests

Do you have any conflicting interests? *