Written by:
Senior Director, Imaging Sciences, AstraZeneca
A new advance in mass spectrometry imaging enables the tissue mapping of large molecules and drug complexes that were previously too large to detect. With applications from drug efficacy to drug safety, this approach can yield a deeper understanding of disease mechanisms and therapeutic interventions.
Learn more about how mass spectrometry imaging enables the analysis of large molecules and intact drug complexes within tissue in the below video:
New imaging method allows for the characterisation of protein-drug interactions
Mass spectrometry imaging (MSI) is a powerful method used to analyse the spatial distribution of molecules, lipids and metabolites in various tissues. Connecting the metabolic landscape within a tissue microenvironment with drug distribution and cellular biomarkers, has changed the way we think about tissue samples.
In drug discovery we have applied MSI to study small molecule metabolite interactions with drug molecules. However, as we expand our chemistry toolkit to include new drug modalities, such as advanced biologics and nucleotide-based therapeutics, it is important we develop new ways to visualise their target interactions across the tissue landscape.
In a longstanding collaboration with University of Birmingham, we have already begun developing new techniques in molecular imaging to address these challenges and bridge the gap between imaging small molecules and larger proteins. In our newest high-impact publication, published recently in Angewandte Chemie, for the first time, we have gone even further to perform in situ analysis of an intact, non-covalently bound protein-drug complex formed in vivo.
To perform this study, we used native ambient mass spectrometry to analyse frozen tissue sections from rats that had been orally dosed with bezafibrate, a small molecule drug that non-covalently binds to fatty acid binding protein 1 (FABP1) in the liver. Unlike other methods, native ambient mass spectrometry does not require digestion or degradation of the molecules prior to detection. Instead, it allows for the ionisation and detection of intact proteins, and in this case, non-covalently bound protein-drug complexes – like freezing them in time when these interactions occur. This approach allowed our team to gather structural information on the relative abundance and spatial distribution of the intact protein-drug complex formed by bezafibrate non-covalently binding to FABP1.
Paving the way for novel therapeutic development
This collaborative research paves the way to quantitatively study large molecules and drug complexes in tissue in ways that have not yet been possible. These new investigational tools have direct implications for drug discovery. By uncovering information on the molecular distribution of large molecules, these techniques could allow for a deeper mechanistic understanding of novel therapeutics such as antisense oligonucleotides and advanced biologics such as antibody-drug conjugates. This research will enable us to reveal even more complex biology and accelerate drug discovery across our disease areas.
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