High Throughput Screening (HTS) has been developed in the 80s, in the context of the automation and miniaturization of techniques for biological assays. Thanks to multiwell plates (96, 384, 1536, or 3456 wells) handled on a platform with robotic arms and automated pipetting systems, it allows to test hundreds of thousands of molecules simultaneously.
Initially, drug discovery was based on the postulate that a disease is caused by a unique molecular dysfunction, as a gene mutation or a dysfunctional mutation for instance. Therefore, molecules were tested on a specific molecular target (enzymatic activity, protein-receptor interaction, etc.): it is the target-based screening.
The phenotypic screening differs from target-based screening, by studying not a specific interaction between a molecule and a specific target, but the final phenotype of the cell. Developed in the 90s, High Content Screening (HCS) is a multi-parametric approach of phenotypic screening, in which a large number of cellular parameters are analyzed (cell viability, specific protein expression, neurite outgrowth, etc.). HCS allows to take into account the resultant of the whole cellular mechanisms, including compensatory mechanisms, and to consider the effect of a molecule as a whole, and not only on a specific target (efficacy and cytotoxicity for example). Therefore, it is particularly valuable in complexes and multifactorial diseases, as neurodegenerative diseases or cancers for example.
A HCS robotic platform (our platform, Fig. 1 below) requires automated microscopes and automatized quantitative images analysis software.
HCS experiments comprise different steps (Fig. 2). Briefly, cells are seeded in multiwell plates. Then, they are incubated with molecules from a library. After incubation, cells can be labelled to study some live cell parameters, as the viability or cell proliferation for example. Then, cells are fixed and stained by immunocytochemistry or fluorescent probes in order to study expression and localization of proteins of interest, of subcellular components… Results are acquired by fluorescence microscopy, and quantitatively analyzed.
HCS Pharma aims at improving the drug discovery process, by combining HCS techniques and 3D complex cellular models, which include not only the cells, but also the matricial microenvironment, thanks BIOMIMESYS® hydroscaffold technology.
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