Bioassays in biodiscovery
Biodiscovery, the exploration of biodiversity, to detect natural products with biological properties, requires a multi-disciplinary commitment to guide biodiversity choices through bioassays and chemistry. We have focused on innovative biology, using high content read out methodologies, across the indications of cancer, infectious diseases (bacterial, fungal, parasitic and viral), diabetes and obesity, inflammatory conditions, and CNS-related diseases. More than eighteen assays have been identified and regrouped around these indications. Most are in vitro cell-based functional assays, with validated molecular targets of high to very high interest. The Institute for Molecular Bioscience (IMB) is also the repository of several chemical libraries containing thousands of yet undescribed chemical structures available for screening. These include marine and bacterial natural products, venom extracts and „combichem“ libraries. Two examples of cell-based assays and one example of purified target-based assay, successfully used against these libraries, are presented: glycine-gated chloride channel inhibition assay (CNS-related indication), tumour necrosis factor alpha (TNFα) trafficking/delivery assay (inflammation) and pneumococcal surface antigen A (PsaA) competitive zinc binding assay (antibacterial). The first two assays are high-content-screenings. Their low-throughput (180 extracts tested per week in duplicate) is compensated by a high frequency of active extracts identified (˜ 0.8%). Cell-based assays show surprisingly good robustness with natural extracts (cytotoxicity, reproducibility) and good signal-to-noise ratio. The last assay in a 384 well plate format uses recombinant PsaA, a fundamental determinant of Streptococcus pneumoniae virulence. Here again, a number of active extracts containing a new class of allosteric inhibitors were identified.
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