Biomolecular condensates: new opportunities for drug discovery and RNA therapeutics

Abstract

Biomolecular condensates organize cellular functions in the absence of membranes. These membraneless organelles can form through liquid-liquid phase separation coalescing RNA and proteins into well-defined, yet dynamic, structures distinct from the surrounding cellular milieu. Numerous physiological and disease-causing processes link to biomolecular condensates, which could impact drug discovery in several ways. First, disruption of pathological condensates seeded by mutated proteins or RNAs may provide new opportunities to treat disease. Second, condensates may be leveraged to tackle difficult-to-drug targets lacking binding pockets whose function depends on phase separation. Third, condensate-resident small molecules and RNA therapeutics may display unexpected pharmacology. We discuss the potential impact of phase separation on drug discovery and RNA therapeutics, leveraging concrete examples, towards novel clinical opportunities.