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CRISPR screens and novel drug targets

According to a new study, a metabolic enzyme studied in cancer biology is key for T-cell function, offering a novel target for anti-inflammatory therapeutics. Dr Jeffrey Rathmell and Ayaka Sugiura from Vanderbilt University in the US discuss their study with Drug Target Review and why inhibiting or genetically deleting the enzyme, called MTHFD2, reduced disease severity in multiple inflammatory disease models.

Metabolic pathways – the chemical reactions that support life – influence immune cell function. In the new study from Vanderbilt University, published in the journal Immunity,1 the researchers focused on “one-carbon” metabolism, a series of reactions that generates chemical building blocks for the biosynthesis of DNA and other molecules.

According to Rathmell, one-carbon metabolism has been a target for drug development for many years, but it has not been fully explored in an unbiased manner. For example, the immunosuppressant drug methotrexate inhibits an enzyme in the one-carbon metabolism pathway, but this may not be the right target or drug for optimal therapeutic activity.

“Metabolic enzymes and pathways play central roles in the biochemistry of how cells interpret their microenvironment. In addition to supporting bioenergetics and biosynthesis, they also support a wide range of cell signalling and gene expression processes,” said Rathmell. “Metabolic enzymes, such as several in the one‑carbon metabolism pathway, are drug targets, but…

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