Identification of novel bioactive substances on brain receptors
Summary
The hurdle of unravelling Nature’s bioactive compound complexity
In search of bioactive compounds, many exogenous natural compounds were demonstrated valuable medicinal starting points and tools for fundamental research. Newly discovered endogenous compounds with specific signalling functions can reveal insights into our body’s functioning and as a consequence, disease mechanisms. Despite this, breakthroughs in these areas are scarce. The main bottleneck here lies in the enormous technical difficulty to profile medicinal targets, i.e. cell-surface receptors and ion channels, against complex natural sources.
Cells on the move to hunt for new compounds
The main disadvantage when using traditional methodologies for profiling complex bioactive extracts is the correlation of the bioactives present with their identity. To overcome this, the current project aims at integrating chemical analysis and biological cellular screening using cell-surface receptors on a single instrument platform.
The need to unravel Nature’s sources for fundamental research
In this study we will use two types of compound resources, one of moderate complexity (i.e., snail venoms containing bioactive peptides), and one of very high complexity (i.e., the brain containing hidden bioactive molecules). Predatory cone snails posses venoms that contain up to hundreds of conotoxins/conopeptides with remarkable ion channel specificities and potencies. For fundamental studies on heterogeneous ion channels, new subtype selective (allosteric) modulators are of great interest. Efficient analysis with the proposed platform will reveal the identity and biological properties of the majority of conopeptides. These valuable compounds will then be studied in depth as new handles to unravel the functioning of brain-residing ion channels.
Secondly, the proposed platform will be used to look deeper into compounds of the mammalian brain than ever before. Here, the discovery of yet unknown endogenous ligands with possibly new subtype selectivities or subtle allosteric actions can be anticipated. New ligands will be studied further in the context of neuronal circuitry function and might eventually allow us to better understand ion channel functioning and relate this to ‘channelopathic’ diseases in the brain.
