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Condensate-modifying therapeutics (c-mods), comprising low-molecular-weight compounds (~1.5 kDa) and related agents such as RNAs and metabolites like ATP, are emerging as promising drug candidates for neurodegenerative disorders, cancer, and viral infections. These compounds modulate liquid-liquid phase separation (LLPS), a biophysical process driven by intrinsically disordered regions, low-complexity domains, and multivalent non-covalent interactions (hydrogen bonds, van der Waals forces, hydrophobic, and electrostatic interactions). LLPS governs the formation of biomolecular condensates essential for gene regulation, signaling, stress responses, and cellular organization. By selectively inhibiting or promoting condensation, we show that c-mods offer strategies to manage diseases presented with aberrant phase separation. Mechanistic insights into LLPS dynamics provided by specific physicochemical features (planar structures and polarity) of c-mods open avenues for accelerating drug discovery, repurposing, and synergistic therapies. We highlight scaffolds, charged molecules, and ions that modulate LLPS. We integrate recent advances in understanding the roles of c-mods in regulating viral protein assemblies; however, the function of LLPS and its regulation in other microorganisms remains underexplored. Future directions include engineering peptide-based therapeutics, designing artificial condensates, and employing AI-driven target identification to discover novel LLPS-associated drug targets. Additionally, biomaterials and industry-led initiatives in condensate-targeted drug discovery are broadening therapeutic intervention across diverse diseases.
Usman et al. (Sat,) studied this question.