Application Note


Cellular metabolism a new avenue in drug discovery


F


inding novel druggable targets for therapeutic intervention is a major priority in building a robust drug dis-


covery pipeline. Now, with a better under- standing of the critical role of metabolism in diseases, researchers are approaching tar- get identification in a whole new way. Agilent’s cell analysis portfolio provides tools to investigate metabolic targets more effectively for a range of diseases, paving the way for cellular energy metabolism as a new avenue for drug discovery. Often thought of as simply providing ‘housekeeping’


functions, energy


metabolism is now known to be a critical contributor to many cellular functions. What’s more, a growing number of differ- ent disease states from cancer and diabetes to neurodegenerative disorders are being linked to dysfunctional metabolism. Looking at the genes, proteins and path- ways that modulate energy metabolism is therefore a promising new approach for developing novel therapeutic strategies for a broad range of diseases. In cancer, for example, metabolic dysreg-


ulation is so commonly observed that it is now recognised as an emerging cancer hall- mark1. In fact, the ‘Warburg effect’ where cancer cells increase glycolysis in presence of oxygen, is one of the best-known examples of metabolic dysregulation. This effect results in increased nutrient uptake and pro- motes cellular biomass accumulation, which is an advantage for rapidly proliferating can- cer cells. Therefore, promising targets for cancer therapies include; oncogenes that rewire energy metabolism, intermediates in oncogene pathways and genes, proteins and pathways that are associated with substrate and nutrient transport or utilisation. There is also increasing evidence that


mitochondrial proteins and mitochondrial dysfunction are responsible for the onset of neurodegenerative diseases,


including


Alzheimer’s, Parkinson’s, Huntington’s and amyotrophic lateral sclerosis. Neuronal cells have high energy demands that mostly depend on oxidative metabolism; conse- quently these cells are highly dependent on mitochondrial function for survival2. Identification of specific proteins affecting mitochondrial metabolic function could therefore provide insight into potential drug targets for neurodegenerative disease. Mitochondrial dysfunction has similarly


emerged as a common thread among metabolic syndromes. One of the key drivers of obesity, excessive nutrient and substrate availability, has a cascade of effects, includ- ing increased adipose tissue, inflammation and insulin resistance, which can lead to type 2 diabetes and cardiovascular disease3. Modulation of metabolic targets, such as those involved in nutrient uptake or utilisa- tion, to restore the balance of energy home- ostasis to ‘normal’ therefore represents a promising therapeutic strategy for reversing or preventing these damaging syndromes. Traditionally, researchers investigating


metabolism measured enzyme activities, protein levels and concentrations of metabolic substrates such as glucose and lac- tose. But these techniques provided a static view of metabolism, which is a dynamic and rapidly-changing cellular process. Increased interest in cellular metabolism


as an avenue for drug discovery, however, has driven an increase in the use of new technologies, such as Agilent’s Seahorse XF platform, enabling the investigation of metabolism in live cells, while it happens in real time. The Agilent Seahorse XF platform is a


label-free, integrated system that delivers quantitative cell metabolic data with real- time compound exposure kinetics. As an alternative, Agilent soluble sensor assay kits provide a plate-reader ready option for live cell analysis. Both technology plat- forms provide a direct measure of energy metabolism, enabling researchers to cap- ture changes in their cell’s functions and phenotypes, thus facilitating the discovery of potential therapeutics.


References 1 Hanahan, D and Robert, A. Weinberg, Hallmarks of Cancer: The Next Generation. Cell, 2011. 144(5): p. 646-674. 2 Lee, J. Mitochondrial drug targets in neurodegenerative diseases. Bioorganic & Medicinal Chemistry Letters, 2016. 26(3): p. 714-720. 3 Busiello, RA, Savarese, S and Lombardi, A. Mitochondrial uncoupling proteins and energy metabolism. Frontiers in Physiology, 2015. 6: p. 36.


44 Drug Discovery World Fall 2018


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