Liquid-liquid phase separation pathway (LLPS)

Liquid-liquid phase separation (LLPS) is a fundamental biophysical process where proteins and nucleic acids condense into dense, liquid-like droplets, creating membraneless organelles known as biomolecular condensates (Hyman et al., 2014, Annual Review of Cell and Developmental Biology). These condensates, such as the nucleolus, stress granules, and P-bodies, serve to compartmentalize cellular biochemistry, facilitating efficient signal transduction, gene expression, and stress responses (Banani et al., 2017, Nature Reviews Molecular Cell Biology). In various pathologies, particularly neurodegenerative diseases like Amyotrophic Lateral Sclerosis (ALS) and Alzheimer's, the LLPS process becomes dysregulated, leading to the transition of liquid droplets into irreversible, toxic solid aggregates (Alberti & Dormann, 2019, Annual Review of Genetics). Furthermore, aberrant phase separation of transcription factors and signaling molecules is a recognized driver in many cancers (Boeynaems et al., 2018, Trends in Cell Biology). Drug discovery efforts are currently focused on "condensate modulators" (c-mods) that can selectively promote or inhibit phase separation, dissolve pathological aggregates, or alter the partitioning of therapeutic agents into specific condensates (Dewpoint Therapeutics, 2024). Targeting the LLPS pathway represents a novel paradigm in drug discovery, moving beyond individual protein-ligand interactions to the regulation of complex macromolecular assemblies.

Other names

Biomolecular condensatesMembraneless organellesCoacervationLiquid-liquid phase separation

Modulation of the physical properties and formation of biomolecular condensates to restore cellular homeostasis or disrupt pathological signaling.