Using parallel whole-cell phenotypic assays, the GSK HTS diversity set of 1.8 million compounds was screened against the three kinetoplastids most relevant to human disease, i.e. Leishmania donovani, Trypanosoma cruzi and Trypanosoma brucei (which cause visceral leishmaniasis, Chagas disease and sleeping sickness, respectively). Secondary confirmatory and orthogonal intracellular anti-parasiticidal assays were conducted, and the potential for non-specific cytotoxicity determined. Hit compounds were chemically clustered and triaged for desirable physicochemical properties in order to generate representative chemical ‘boxes’, with a maximum of two compounds per chemical cluster per box. Ultimately, three anti-kinetoplastid chemical sets of 222 compounds for Chagas-Box, 192 compounds for Leish-Box and 192 compounds for HAT-Box were assembled as new antimicrobial sets available to external collaborators upon request.
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This is the first published parallel high throughput screening of a pharma compound collection against kinetoplastids. Within an open innovation framework, it has been the result of hand-to-hand public-private collaboration at Tres Cantos Medicines Development Campus between GSK researchers and scientists from New York University, University of Dundee and Instituto Lopez-Neyra of Granada, as well as the support of Tres Cantos Open Lab Foundation. The study, as well as the physical samples of these boxes, provides an open resource for future lead discovery programs and to address important research questions. We are leveraging the discovery and public disclosure of the GSK Kineto Boxes in order to unveil new targets, mechanisms of action and chemical biology knowledge. A collaborative network is emerging thanks to researchers and institutions requesting the Boxes. Expectation is that there will be synergies amongst partners, which otherwise had not happened. Ultimately, we envisage contributing to the research community with new therapeutic targets and chemical tools which may become the source of future drug discovery programs.
Figure 1: Overlapping of compounds in each box (left diagram) and Cross- activity of each compound versus kinetoplastid parasites. Tc: Chagas box (left) and Trypanosoma cruzi activity (right); Tb: HAT box (left) and Trypanosoma brucei activity (right); Ld: Leishmania box (left) and Leishmania donovani activity (right).
1. Peña I, Manzano, MP, Cantizani, J, Kessler, A, Alonso-Padilla, J, et al. (2015) New Compound Sets Identified from High Throughput Phenotypic Screening Against Three Kinetoplastid Parasites: An Open Resource. Scientific Reports 5:8771. DOI: 10.1038/srep08771.
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