Identification and validation of PRMT7 inhibitors as potential novel therapeutics against inflammatory disease
Chronic obstructive pulmonary disease (COPD) is an inflammatory lung disease characterized by progressive and largely irreversible airflow limitation. It is a leading cause of chronic mortality and morbidity worldwide with no current therapies able to reverse disease progression. Cigarette smoke was considered the main cause of development; however, the heterogeneous nature of the disease leaves it certain that other factors contribute to the pathogenesis of disease. Recently, a role for epigenetic modification in the underlying pathology of COPD is emerging. The addition of methyl groups to arginine residues in both histone and non-histone proteins by protein arginine methyltransferases (PRMTs), is an important posttranslational epigenetic modification event. Crucially, we have shown that PRMT7 imprinted methyl-arginine marks in histones regulates the recruitment of monocytes into injured tissue and the pathogenesis of disease development (Nat Communications, 2022).
What will you be working on?
PRMT7 is a unique PRMT, as it is the only enzyme of its family that can imprint just mono-methyl arginine (MMA) modifications and thus guide the activity of other PRMTs. This lends itself as a prime candidate for identifying novel inhibitors of its activity for potential drug discovery programs to elucidate novel anti-inflammatory approaches. To this end we are currently optimizing ALPHA-LISA activity assays utilizing recombinant PRMT7 to enable screening of the small molecule libraries available at the Helmholtz Zentrum München, including the Prestwick FDA approved drugs library. Identification of putative candidates will need to be validated in vitro in cell culture assays for toxicity, the ability to block MMA activity, and downstream readouts of migration ability.
What techniques will you use?
This project will utilize in vitro cell culture assays of cell lines and primary cells. Conventional molecular biological methods (qPCR, western blotting) will be carried out in addition to more specialized methods (FACS and trans-well migration assays). This project will be both stimulating and rewarding for anyone with an interest in lung biology or a general desire to target the molecular mechanisms underlying disease pathogenesis.