Newly Discovered Compound Prevents Bronchoconstriction in Mouse Model
Researchers have discovered a compound with the ability to induce long-lasting bronchorelaxation and prevent hyperreactivity in murine models of asthma. These results present potential for the development of therapeutics against a multitude of breathing disorders. The study was published in Science Translational Medicine, 13th September 2017.
Current treatment regimens for those with breathing conditions, such as asthma and emphysema, involve the use of combination therapies, as G-protein coupled receptors (GPCRs) involved in the development of such conditions are targeted individually. Gq-coupled GPCRs are believed to be involved in the control of airway smooth muscle tone. Airway resistance has been observed upon combined or individual activation of these receptors. Dr Michaela Matthey, Institute of Physiology I, University of Bonn, and collaborators focused on the Gq component of the receptor and demonstrated that protection against bronchoconstriction was possible by pharmacological inhibition of Gq using a depsipeptide, termed FR900359. Multiple GPCRs couple with Gq, therefore it was possible to silence several signaling pathways within the smooth muscle cells through this one central target. This inhibition was observed in pigs and humans as well as mice. FR900359 was also successfully delivered to mice via aerosol inhalation, and its effects persisted for 24 hours.1
Study Limitations and Future Direction
Further animal studies are required in larger models to supplement the data gathered in this study. Focus will also need to be directed towards the exploration of longer-term effects including adverse events and toxicity. The researchers also highlight that in ‘real world’ patients, bronchodilators would be administered to address existing bronchoconstriction, in contrast, during the study in vivo airway resistance measurements only allowed determination of bronchodilation applied before constriction. Delivery method (systemic vs inhalation) is another factor requiring additional testing.1 Although there are a number of factors to consider and additional studies to perform, this study is an encouraging step towards a potential therapeutic strategy, specifically targeting Gq.
We spoke to Dr Daniela Wenzel, last author of the recently published paper, to find out more about the discovery.
LM: Could you provide some more information about FR900359?
DW: FR900359 is a depsipeptide that can be isolated from the leaves of the plant Ardisia crenata (also known as the Christmas berry). It is a highly selective blocker of Gq proteins, which are intracellular signaling molecules.
LM: Could you give us an overview of the techniques used during the study?
DW: In single cell measurements (label-free dynamic mass redistribution and impedance measurements, Ca2+ imaging and cAMP assay) we determined the specificity of FR900359 for Gq inhibition in airway smooth muscle cells. By the use of isometric force measurements we assessed the capacity of FR900359 to induce airway relaxation in mice, pigs and humans. In vivo techniques (Flexivent measurements, catheter analyzes) served to analyze the impact of FR900359 on airway resistance and to exclude cardiovascular side effects i.e. alterations of blood pressure and heart rate. Finally, we examined the airway relaxing effect of FR900359 in murine disease models (ovalbumin-induced or house dust-induced murine asthma models) to determine the therapeutic potential of the compound.
LM: Do you think there is scope to broaden the investigation of FR900359 beyond airway disease? If so, is this something your team will be exploring in future?
DW: We are also going to examine the impact of FR900359 in other types of disease, in which Gq proteins play an important role.
1. Matthey, M., Roberts, R., Seidinger, A., Simon, A., Schröder, R., Kuschak, M., . . . Wenzel, D. (2017). Targeted inhibition of G q signaling induces airway relaxation in mouse models of asthma. Science Translational Medicine, 9(407). doi:10.1126/scitranslmed.aag2288