A new study from the Hsu Lab in collaboration with colleagues at Princeton report the discovery of small molecules capable of controlling cellular levels of membraneless subcellular compartments known as processing-bodies (PBs) and stress granules (SGs). PBs and SGs are cytoplasmic ribonucleoprotein granules that are part of a larger family of structures collectively referred to as biomolecular condensates. These structures can be induced in response to cellular stress for survival, but aberrant condensate regulation is associated with a growing number of disease states including neurodegeneration, viral infection, and cancer. Targeting disease-relevant condensates offers a unique opportunity for therapeutic discovery but has proven challenging because of the compositional diversity and dynamic nature of these evolutionarily conserved structures. In this study, the investigators demonstrated that covalent binding to tyrosine sites on key condensate-forming RNA-binding proteins (RBPs), a class of proteins historically deemed undruggable, can prevent or induce these cytoplasmic structures in stressed cells. The researchers were able to effectively target RBPs using sulfur-triazole exchange (SuTEx) chemistry developed by the Hsu Lab in combination with in-house mass spectrometry-based chemical proteomics capabilities.
The study titled “Global Discovery of Covalent Modulators of Ribonucleoprotein Granules” was led by graduate students Anthony Ciancone and Miaomiao Chen from the Hsu Lab and Josh Seo from the Kleiner lab and published in the Journal of the American Chemical Society.
