Deciphering the Workings of Molecular Bullets – Fast! A High-Throughput Platform for Investigating Biological Mechanisms
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Thomas B. Poulsen
Institution
Aarhus University
Beløb
DKK 4,331,000
År
2017
Bevillingstype
Semper Ardens: Accelerate
Hvad?
Chemical compounds can perturb biological systems - cells or organisms - and the precise manner, in which they do is referred to as their mode-of-action (MoA). MoA-studies are often rate-limiting in the development of new bioactive compounds that could e.g. find use as molecular tools in cellular biology. We will establish an experimental method - called morphological profiling - for making "fingerprints" of bioactive compounds that can be used to gain MoA-information. For instance, similarity between the profiles of an unknown and a well-studied compound indicates that they impact the same cellular processes. Conversely, a unique profile indicates a unique MoA. When scaled to large databases of profiles, this method enables MoA-hypotheses to be generated for any new bioactive compound.
Hvorfor?
Alternative profiling methods have previously been used to gain MoA-information, but the transformative aspect of morphological profiling is its high speed and low cost. Whereas MoA-studies previously were only prioritized for a few or even just one bioactive compound within a family, we will now be able to test all analogs as well synthetic intermediates that will e.g. be made during efforts to chemically construct a molecule of interest. In other words, we will be searching for new biological activity (new MoA's) in places that would otherwise never be considered and this potential for discoveries is a very important aspect. Two interesting molecular families will be studied as part of this project, but the perspectives reach much further.
Hvordan?
The project will commence with the purchase of a high-throughput microscope needed to establish the morphological profiling method. We will then prepare a series of structural analogs of two different bioactive compounds, one of which is quite toxic to cancer cells while the other is known to stimulate the growth of nerve cells, but common to them is a lack of knowledge about their specific MoA. Morphological profiling of these collections of compounds will allow us to master the method and to learn how the changes in structure impacts the profile and thus alters the cellular activity. We will then combine morphological profiling with other methods to conclusively delineate the MoA for these two compounds.