Our previous research found that propofol has a significant effect on presynaptic release mechanisms, which presents new approaches to uncovering reversal agents. Here, we investigate a promising candidate reversal agent: a fluorinated analogue of propofol called propofluor. We cover two different levels of investigation: molecular biology and structural biology.
The investigators will use in vitro cell culture methods to study how propofluor might be overturning the effects of propofol on neurotransmission. This involves two levels of imaging: quantifying neurotransmitter release from neurosecretory cells and tracking presynaptic protein dynamics in these same cells. Single-molecule imaging readouts provide information about the effects of propofluor on two known interacting protein targets of propofol in the synaptic release machinery, syntaxin1A and munc-18.
Proteomic analysis of drug binding to amino acid residues will reveal structural mechanisms of drug action, informing how propofol and its analogue propofluor might interact with presynaptic proteins of interest. The results from this objective will provide insight into whether propofluor is binding to the same targets as propofol, highlighting if there are competitive binding sites and thereby uncovering a potential presynaptic mechanism of action. We will be studying these proteins in the same neurosecretory cells, to provide an explanation for our functional observations.
The benefit of this basic neuroscience research is to find anaesthesia reversal drugs that ‘work’, and knowing why they work, as a necessary prequel to further pre-clinical testing.
Professor Andre van Zundert, Royal Brisbane and Women’s Hospital, Queensland.
Associate investigators:
Professor Bruno van Swinderen, Queensland Brain Institute
Professor Victoria Eley, Royal Brisbane and Women's Hospital, Queensland.
The project was awarded A$70,000 funding through the ANZCA research grants program for 2024.